Appendix

Human and Rat Liver Cytochromes P450: Functional Markers, Diagnostic Inhibitor Probes, and Parameters Frequently Used in P450 Studies

Maria Almira Correia

The tables in this appendix summarize the rel­ different P450 isoforms included in its evaluation ative functional selectivities of substrates and as well as the range of substrate/inhibitor concen­ inhibitors for the major human and rat liver trations tested. Second, substrates and inhibitors C3^ochrome P450 isoforms (P450s). These hepatic determined to be "relatively selective" for a human isoforms are well recognized to catalytically par­ liver isoform, may not necessarily be so for its rat ticipate in the metabolism of chemically diverse liver ortholog, and vice versa. Third, the relative endo- and xenobiotics including drugs, and in the metabolic contribution of a P450 isoform to the case of human liver P450s to thus contribute to in vivo hepatic metabolism of a given drug is directly clinically adverse drug-drug interactions. Conse­ proportional to the relative hepatic microsomal quently, these P450s are the targets of intense abundance of that isoform and its affinity for that scrutiny in the pharmaceutical screening of exist­ compound, irrespective of its in vitro high meta­ ing or novel chemical agents of potential clinical bolic profile assessed under "optimized" condi­ relevance for drug development. At a more basic tions. This issue arises because recent advances in level, these tables provide information on estab­ recombinant P450 technology have made unprece­ lished and/or potential diagnostic tools for the dented amounts of purified human liver enzymes identification and/or characterization of the meta­ readily available for comparative in vitro charac­ bolic role of each individual P450 in the disposition terization of drug metabolism, at relative P450 of an as yet uncharacterized xeno- or endobiotic. concentrations that may be irrelevant in vivo. Three critical issues are however worth considera­ Furthermore, this abundance albeit highly desir­ tion before use of these experimental probes: First, able, has nevertheless also sidelined the compara­ as discussed in Chapter 7 (Inhibition of Cytochrome tive characterization of rat liver orthologs of newly P450 Enzymes), given the vast diversity of P450 discovered human P450 isoforms. Thus, in some isoforms and their differential active-site affinities cases (i.e., CYPIBI), better characterized func­ for a given compound, the "relative" selectivity tional probes are available for the human liver of a substrate or inhibitor probe for a given P450 enzyme than for its rat counterpart. In addition to isoform is entirely defined by the number of the functional probe information, a table with

Maria Almira Correia • Departments of Cellular and Molecular Pharmacology, Pharmaceutical Chemistry, and Biopharmaceutical Sciences and the Liver Center, University of California, San Francisco, CA. Cytochrome P450: Structure, Mechanism, and Biochemistry, 3e, edited by Paul R. Ortiz de Montellano Kluwer Academic / Plenum Publishers, New York, 2005.

619 620 M.A. Correia some signature P450 spectral characteristics and Biology (Volume 107, Cytochrome P450 parameters commonly used in P450 studies has Protocols)^, Chapter 7 (Inhibition of Cytochromes been included as a quick reference guide. P450), and Chapter 10 (Human Cytochrome P450 It is to be noted that the tables in this appendix Ervz^mQs). Last, but not the least, I wish to partic­ have been compiled with practical utility rather ularly acknowledge Prof S. Rendic for having pro­ than comprehensiveness as the overall objective. vided access to his regularly tipdated human P450 Much more comprehensive coverage is available in metabolism database through the Gentest website several excellent books and reviews on human and during the preparation of this Appendix. Wherever rat liver P450s that are gratefully acknowledged as feasible, the literature citations in this appendix the sources of some of the information presented have favored those providing methodological herein^"^^. In particular, the reader is referred to details, assay modifications, and/or controversial the series Methods in Enzymology (Volumes 10, information, sometimes at the expense of accurate 52, 206, 272, and 357)3-^, Methods in Molecular chronological reporting of the literature. Human and Rat Liver Cytochromes P450 621

2 ^ 45 g .. & *o 2^ o i I 1

u 1^ ^ > O 4D o "O^ fl e OH ^^ 1 1 1 •S ^C3 oc &>§>•§»& s §2 S PQPQ "b 11cS 2^ o 1 "s Hill, &o en en ii o '5b I 3 u S" 5^ O PM a 03 s + s ^ o III to il c> '5 3 ^ PsH o cN CO H H U H GO H H O^PLHC/3 O s S ^u *w.^a A % ^ ci 1 fl sO o iz; T3 CD fi fl P A ^3 EaM ,a ^b W O I.S o ^ OH K) 2'^ O SH -O^H PA ^ fl I £2 III 9 o >- TJ '2 w ao a 0 Q I 2 ^^a .§ < a J) o 13 r ^2 5 ^ .S q:: « r5 ^ gag ^

©

o

Sc o wQ Qw i • [X] ' I 2 c ts

4^ 3 -« O fl I U

•s g 11 i Si

8 Is

It CO > o 1 " _o o ^_^ I 2^ I II til

£^1 PQ (N PH

00 o m ^

I/) in r-- TH < PQ CM <

»^ >^ o ed o O o

-S. o .

o lis c 1^^ T3

S s= 5 OH •2II •-^ O T3 <:|.^ ^ J*- ^ o £.§

;^'5 2 o2 a. •S B , . > ^ «3 ex I D ON is ^ OTS ^ O p o ^ ^a

3 . CM . -5 ^ •-d W N 72 g •o' o""^ O ?'^ 3 (N O ^^ ^ ,—^ 13 «2 "flj "o O lo gj S.2 c^ o^ -O c3 ^ .1^ •-^ fl .1 ^^g ^ 3;-5^2:: 2LVON . .^-' o c I oo ;i O cp Os^ § -^ ^. JIJCN ^ r r- a —"—' 03'—"—i"- "S P^ OO -^ ^ t^ rr^^ eg c^ .g .£2 ^ ci -i-"^(-(M-Hj< >"-'

Table A.2. Human Liver P450s: Chemical Structures of Diagnostic Substrate and Inhibitor Probes

P450S Substrate^ Inhibitor^

CYP1A2

OH O Galangin (3, 5,7-trihydroxyflavone)^ ^^

CH3CH2'

Ethoxyresorufin^o^^ Furafylline (MBI/S)3^ ^2

^H—COCH3

CYP2A6 NH.

o^^o .HCl

Coumarin'^ Tranylcypromine'^' '*^^^ x)^

(R)-(+)Menthofuran (MBI/S)"^ Human and Rat Liver Cytochromes P450 625

Table A.2. (continued)

P450s Substrate^ Inhibitor^

CYP2B6

O' XH3 (S)-Mephenytoin^^ 2-PMADA^'^52

Bupropion hydrochloride^' 3-PIVIDIA^

9-Ethynylphenanthrene (MBI/S)^^^

/CI ,x^^\^Sv ' J. Ticlopidine (MBI/S)' CYP2C8 ^^^ JD OH CH \==/ NH

Taxol (paclitaxel) ^^^^ CYP2C9

^"•-v/fv^^ O CI Tolbutamide ^ Tienilicacid(MBI/Sp,73 626 M.A. Correia

Table A.2. (continued)

P450s Substrate^ Inhibitor^

COOH '^-vjhQ"

Diclofenac ^^ ^"^ Sulfaphenazole^

CYP2C18

3-[2, 3-Dichloro-4-(2-thenoyl)phenoxy]- propan-1-or^

CYP2C19

(S)-Mephenytoin7i^4,8o^i (+)-A/-3-Benzyl-nirvanol'^'

(+)-A/-3-Benzyl-phenobarbital^

CYP2D6

4 > NH . II N—C—NH2 Debrlsoqulne^^^^ Quinidlne^^9,9o Human and Rat Liver Cytochromes P450 627

Table A.2. (continued)

P450S Substrate" Inhibitor^

\>—CH—CH2—NH—C—CHg CH3

(+/-) Bufuralor SCH66712^^96

c„.o^J>-o

CH3O -^^^ Dextromethorphan Hydrobromide^"^ ^^ Paroxetine (l\/IBI/Qlf

CYP2E1 H 1> CH3 Chlorzoxazone 97-99 4-l\/lethylpyrazole^^9^^^

(CH3)2N—N=0 (CH3CH2)2N-C-SH yV-Nitrosodimethylamine^^^^°^ Diethyldithiocarbamate^^ ^^^ ^^^

CYP3A4

CH3

CH3

X Testosterone^o^^^^ Azamulin"^ 628 M.A. Correia

Table A.2. (continued)

P450s Substrate^ Inhibitor^

OH CH3^.^-^^OCH3 I >CH3 H3C

CH3 ^ H3C' ^O ^ OH I/CH3

OHCH3 \^^^0C0CH3 6CH3 Erythromycin 116,117 ^^3 Troleandomycin (MBI/QO^i^ ^^^

H3CO2C

Nifedipine' Gestodene (MBI/S)

KetoconazoleA18,48' , 115, 122 Human and Rat Liver Cytochromes P450 629

Table A.2. (continued)

P450s Substrate^ Inhibitor^

f<::^=^^^^N-0CH3

V-OCOCHa

H3C CH3 Midazolam'' Diltiazam (MBI/QI)^ ^^e

CYP3A5

%^ Midazolam^ 128,129,131

OCH3 Aflatoxin BV 630 M.A. Correia

Table A.2. (continued)

P450S Substrate^ Inhibitor^

CYP3A7

HO3SO DHEA-Sulfate'

CYP4A11 COOH

COOH

Laurie acid ^ 17-0DYA(MBI/S)>

^^N^^N'°"

HET0016^^^^^2

~\- COOH \ H 10-IDA^^ 141 Human and Rat Liver Cytochromes P450 631

Table A.2. (continued)

P450S Substrate^ Inhibitor^

CYP4F2 OH

COOH

10-UDYA(MBI/Sr

CYP4F12 OOH

Arachidonic acid^"^^

CYP7A1

Cholesterol^

CYP8B1

3-One-4-ene-7a-hydroxycholesterol 632 M.A. Correia

Table A.2. (continued)

Additional literature references are listed in Table A.2. "Arrow(s) indicate(s) the substrate position(s) oxidized by that particular P450 isoform, enabling the assay of the corresponding oxidized metabolite(s) as its relatively selective functional probe(s). *The arrow indicates the inhibitor site that is metabolically activated by that P450 isoform resulting in mechanism- based inactivation (MBI) of the enzyme that is either irreversible (suicide, S) or quasi-irreversible (QI). ^Inhibitor acts competitively by coordinating to the P450 heme-iron and/or ligation to the protein at the active site. ^2-PMADA, 2-isopropenyl-2-methyladamantane. ^3-PMDIA, 3-isopropenyl-3-methyldiadamantane. ^SCH66712, 5-fluoro-2-[4-[(2-phenyl-1 H-imidazol-5-yl)methyl]-1 -piperazinyl]pyrimidine. ^A metabolic intermediate complex (MIC) observed only with CYP3A4 but not CYPs 3A5 and 3A7. ^Given their —89% sequence similarity, CYP3A4 and CYP3A5 have similar functional and inhibitory profiles. However, CYP3A5 may be distinguished from CYP3A4 by its higher metabolic ratio of midazolam 1 '-/4-hydroxyla- tion, aflatoxin Bl 8,9-epoxidation to 3a-hydroxylation, and alprazolam 4-/1'-hydroxylation, as well as by its inabil­ ity to form a diltiazam-MIC. Mifepristone has also been found to distinguish between the two CYP3A isoforms. 'DHEA-sulfate, dehydroepiandrosterone sulfate. ^17-ODYA, 17-octadecynoic acid. (Ortiz de Montellano, personal communication) ^ETOOl 6, A^-Hydroxy-A'^'(4-butyl-2-methylphenyl)-formamidine. ^10-IDA, 10-imidazolyldecanoic acid. '"LTB4, leukotriene B4. "10-UDYA, 10-undecynoic acid. (Ortiz de Montellano, personal communication)

Table A.3. Rat Liver P450s: Chemical Structures of Diagnostic Substrate and Inhibitor Probes

P450s Substrate^ Inhibitor^

<^YP1A1 NH-COCH3 H0\

Acetanilide^^^ Rhapontigenin(MBI/S)^^^

(R)-Warfarin^5^6^^i

7-Ethoxyresorufin^ 40,41 (O-Deethylation) Human and Rat Liver Cytochromes P450 633

Table A.3. (continued)

P450S Substrate^ Inhibitor^

CYP1A2 Caffeine^' ^^ Galangin (3,5,7-trihydroxyflavoneyf-e, 38 (N'Demethylation)

Theophylline^ Furafylline (MBI/S)^

\ CH3O

7-Methoxyresorufiin40,4n i

Phenacetin"^ ^^2 (O'Deethylation)

CYPIBI CH3OH

CH3O

-OCH3

"OCH3 TMS (2, 4, 3', 5'-tetramethoxystilbene)i^4

7-Ethoxyresorufin^ ^' i54^i56 (O-Deethylation)

CYP2A1 9^3 PH

Testosterone^ 634 M.A. Correia

Table A.3. (continued)

P450S Substrate^ Inhibitor^

CYP2A2

Testosterone'^^ '^^

CYP2B1 9^3 OH

Testosterone'* Secobarbital (MBI/S)'^^ '^^

BK\ y/"CH2CH2—NH—C—CHCI F O ^ A/-2-P-BPCFA (MBI/S)'68

\ CH3CH2CH2Cn2CH2 ^^2 \ y-CH2CH2—NH—C—CHCIF O "X 7-Pentoxyresoruf in' A/-2-P-NPCFA (IVIBI/S)'68

9-Ethynylphenanthrene (l\/IBI/Sy ,169.

CYP2C6 2ICH3 CH2 C—H

Progesterone 171,172 Pregn-4,20-diene-3-one (l\/IBI/S)' Human and Rat Liver Cytochromes P450 635

Table A.3. (continued)

P450S Substrate^ Inhibitor^

(S)-Warfarin^5^6^5i Sulfaphenazole"^

CYP2C7 Testosterone^ 1^2, i63 (16a-Hydroxylation)

Progesterone^' ^^^ (16a-Hydroxylation)

CYP2C11 9"3 PH

COOH

Testosterone^^^' ^^^ Diclofenac (l\1BI/S)^

CYP2C12 CH3 ^"^C-0

Progesterone^^^

OSO3H

HOaSO-^

5a-androstane-3a,17pdiol, 3,17-disulfate^^^

CYP2C13 Testosterone"^ ^^°^^^ (6p'Hydroxylatlon) 636 M.A. Correia

Table A.3. (continued)

P450S Substrate^ Inhibitor^

CYP2D2 CH3 NHCH3 NHCO—CH^-N(CH2CH3)2

4-Allyloxymethamphetamine(MBI/S)^^^

Debrisoquine (4-Hydroxylationy ^^^

(+/-) Bufuralol (T-Hydroxylationy ^^9, iso

CYP2E1 ^H=CH CI Chlorzoxazone"^ ^^^ ^^2 trans'^ ,2-dichloroethylene (MBl/S)^^^ (6-Hydroxylation)

/V-Nltrosodlmethylamine^ 100, i84, i89 DIallylsulfone (MBI/S)^ 186-189 (N-Demethylation)

CYP3A2/3A23 CH3

Testosterone^' i^^, i63,190 ep-Thiotestosterone (MBI/S)^- Human and Rat Liver Cytochromes P450 637

Table A.3. (continued)

P450s Substrate^ Inhibitor^

Erythromycin^' ^^^ 2p-Thiotestosterone (MBI/S) 191 (N-Demethylation) Nifedipines^ ^2 Troleandomycin {MB\/Q\y (Oxidation)

CYP3A9 2rcH3

Progesterone^^^, 195 (6p, 21-Dihydroxylation)

CYP4A1 Laurie acid^ ^^^ 17-ODYA"'(MBI/S) ^(o -Hydroxylation)

CYP7A1 Cholesterol^ 199,200 10-UDYA"'(MBI/S),c , 197, 198 (7oL-Hydroxylation)

^The arrow(s) indicate(s) the substrate position(s) oxidized by that particular P450 isoform, enabUng the assay of the corresponding oxidized metaboHte(s) as its relatively selective functional probe(s). *The arrow indicates the inhibitor site that is metabolically activated by that P450 isoform resulting in mechanism- based inactivation (MBI) of the enzyme that is either irreversible (suicide, S) or quasi-irreversible (QI). '^The chemical structures is depicted in Table A.2. The reaction used as a functional probe is shown in parentheses. ^A polyclonal anti-rat CYPl Al antibody is available that recognizes CYPl A2 in immunoblotting, but that selectively immunoinhibits CYPlAl but not CYP1A2 function. ^Inhibitor acts competitively by coordinating to the P450 heme-iron and/or protein binding at the active site. ^Steroid structure and site of 16a-hydroxylation shown under CYP2C11. Lower activity than that of CYP2C11. ^Phenethylisocyanate is also reported to selectively inhibit this enzyme^ ^9. ^Progesterone or androstenedione 6p-hydroxylase may also be used as functional probe^^^, ni '17-ODYA, 17-octadecynoic acid. (Ortiz de Montellano, PR., unpublished observations). ^10-UDYA, 10-undecynoic acid, (Ortiz de Montellano, PR., unpublished observations). 638 M.A. Correia

Table A.4. Commonly Used P450 Substrates and Inhibitors

Trivial name Chemical structure Type of oxidation P450 catalyst(s)

A. Substrates

Acetaminophen!^^ 200,201 iV-Oxidation CYPs 2E1,3A, 1A2 NH—COCH3

OH

Aminopyrine^^!' ^^^ A^-Demethylation Multiple CHa JS1/CH3 CH3

CHa

Androstenedione^^^, i63 C-Hydroxylation Multiple

Aniline! C-Hydroxylation Multiple

Benzphetamine^^! 203 /=^=\ CH3 /=\ iV-Demethylation Multiple \j-'ytt^ Human and Rat Liver Cytochromes P450 639

Table A.4. (continued)

Trivial name Chemical structure Type of oxidation P450 catalyst(s)

Benzo(a)pyrene^^^' ^^"^ C-Hydroxylation CYPs lA, IB

7-Ethoxycoumarin i ^ i, 205 ^ O-Deethylation Multiple

CH3CH20.,^^;s>ss^O\^0

^^^^^^^

7-Ethoxy-4- O-Deethylation Multiple trifluoromethyl- coumarm 26,53 CH3CH2'

Ethylmorphine ^ iV-Demethylation Multiple CH3

CH3CH2O O OH

/j-Chloro-A'-methylaniline iV-Demethylation CYPs lA (PCNMA)206 HCH3

CI 640 M.A. Correia

Table A.4. (continued)

Trivial name Chemical structure lype of oxidation P450 catalyst(s)

/;-Nitroanisole^^^ O-Demethylation Multiple CH3

NO2

Progesterone^ ^^ C-Hydroxylation Multiple 2rCH3 ^ c=o

Testosteronei60-i63, i90 C-Hydroxylation Multiple '3 OH

(i?/5)-Warfarin^ C-Hydroxylation Multiple

/ X Human and Rat Liver Cytochromes P450 641

Table A.4. (continued)

Trivial name Chemical structure Modeof inactivation P450s inactivated

B. Inhibitors Allylisopropylacetamide^^^ MBI/S Multiple / H2

1-ABTb 207-209 NH2 MBI/S Multiple N > N

7,8-Benzoflavone^ CYPs lA, IB

Carbon monoxide^' ^ C=0 Multiple

Cimetidine^,210-21 3 H H C Multiple N—TT-CHz-S-CHa-CHg-N-C-N-CHa MBI/QI CYPs 2C6 and 2C11 / \ NC=N

DDEP^ HV/CH2CH3 MBI/S Multiple CH3CH202CN,^^^\S-^C02CH2CH3

H3U l^ CH3 H

Ellipticine^ CYPs lA, IB, 2A6 642 M.A. Correia

Table A.4. (continued)

Trivial name Chemical structure Mode of inactivation P450s inactivated

Fluvoxamine^^^'^^^ CYPs 1A2, 2C19,2C9

F3C-/ V9(CH2)40CH3 N—O—CH2CH2NH2

Ketoconazole^ Multiple^

I—COCH3 "6°

8-Metlioxypsoralen^ MBI/S Multiple^

Metyrapone^^^' ^^^ Multiple

N= V_/S-EO

Piperonyl butoxide^^^' ^^"^ MBI/QI Multiple Human and Rat Liver Cytochromes P450 643

Table A.4. (continued)

Trivial name Chemical structure Mode of inactivation P450s inactivated

SKF525A^225 .^^^^ MBI/S Multiple

CH3CH2CH2-C-C-0-CH2-CH2-N(C2H5)2HCI

"C, competitive inhibition through P450 Fe'''VFe"'"^-heme complexation; MBI, Mechanism-based inactivation that is either quasi-irreversible (QI) via metabohc intermediate complexation or irreversible (suicidal, S). * 1 - Aminobenzotriazole ^DDEP, 3,5-Dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine. ^Potent inhibitor of CYP3A4, but can inhibit other P450s at higher concentrations. Nonselective for rat liver P450s. ^Potent inhibitor of CYP2A6, but can inactivate other P450s at higher concentrations. /SKF525A, Proadifen hydrochloride 644 M.A. Correia

11 ^ ^ S I ^H T3 >—r U 5 O c/5 U ^ I 5l <^ o ^'^ ^ rj- OH ^ 5S ^ s CQ L_J •^;4_> p?. s > ^ O »^ s irt o

0^ o o o^ r>4 ) rvj '-H m ^^ '—1 ^^ ^ ( '^ OS (N OO Tf ^

O o OS o OS E OS

c/3 CO. d c/5 1 r- ^ -^ '^ Tf »r> CN OS »^ ^ CO r^ Tt «ri CO u^ VO rj- lo Tf Tt o

< t:^ 9^ •\ O ,i> '^o O < t/5 .(0 U ^ -^ T2 ? S ? S ? 5 + < + <^Q fs" .1 w •« V. •«««* s: IN 4> Q t> ;j sA k^ ^ CQ «^ PLH >0^ Human and Rat Liver Cytochromes P450 645

o

•e* o a> ys > ^ o , x^ t3<: o -g o o a CO U

&~ -SB 5SJ P(^ PilH

O o o o U^ '—1 O ON ON OS OS r- Tt o ^ ^ Tf to u^ ^

lyj GO. d c/3 oQ. d o O OS ^H 00 iTi I CO «o *o »o to u-^ Ti" in »o m »o to §^ I & S S + 0) J CD 6^ (D CO + 1 ;^ pL, < ;^ I ^ I s i I I S I I 646 M.A. Correia

— w OH

(U Ok & a o .c 4> (Z> -w B CS "oS 'B c« S S fi 43 CO "B M o iCsA (U (U OH (X J3 (73 ,fi "o^ ex on s _B^ a. o 1/3 o CA K (N JP ^ "o 13 TS e3 S "^ X> £1 O 1 g X o •g 1o OQ 'S U Di^ PH fe < g

O s <

s 3

r- ro O u-^ Tf vo ^ yn o »n ^^ m vo

to I « (U a> (u 5+ : § I •I i .5 s 2 I I Human and Rat Liver Cytochromes P450 647

1. Estimation of Cytochrome 2. Sato, R., T. Omura, Y Imai, and Y. Fujii-Kuriyama P420 in Cytochrome P450 (eds) (1987). Cytochrome P450: New trends. Yamada Science Foundation, Japan. Preparations 3. Estabrook, R.W. and M.E. Pullman (eds) (1967). Methods in Enzymology Volume 10: Oxidation and Using the spectral baseline correction mode, Phosphorylation. Academic Press, New York, NY. determine the peak spectral absorption differ­ 4. Fleischer, S. and L. Packer (eds) (1978). Methods in ences (AA) between 420-490 nm (P420) and Enzymology, Volume 52: Biological Oxidations, 450-490 nm (P450) of CO-reduced-reduced Microsomal cytochrome P450, and other hemopro- tein systems. Academic Press, New York, NY. (Fe+2C0-Fe+2) samples226,227,233,245 5. Johnson, E.F. and M.R. Waterman (eds) (1991). [P450]: AA45(^9o^/0.091=X nmol/ml (with Methods in Enzymology, Volume 206: Cytochrome P450, Part A. Academic Press, New York, NY. emM'^cm"^ = 91) 6. Johnson, E.R and M.R. Waterman (eds) (1996). [P420]: AA42o^9o„^ ^^-^^^ = ^ nmol/ml (with Methods in Enzymology, Volume 272: Cytochrome emM-^cm-i = 110) P450, Part B. Academic Press, New York, NY. (~0.041)X nmol/ml = correction for negative 7. Johnson, E.R and M.R. Waterman (eds) (2002). Methods in Enzymology, Volume 357: Cytochrome contribution of P450 to P420 peak absorption at P450, Part C. Academic Press, New York, NY. -420-424 nm(emM-icm-i = -41) 8. Phillips, I.R. and E.A. Shephard (eds) (1998). Actual [P420] in P450 preparations: Methods in Molecular Biology, Volume 107: 7-[(-0.041X)/0.110] = Z nmol/ml Cytochrome P450 Protocols. 9. Testa, B. and R Jenner (eds) (1976). Drug Metabolism: Chemical and Biological Aspects. 2. Determination of Cytochrome Marcel Dekker. P450 Reductase Activity 10. Ortiz de Montellano, PR. (ed.) (1986). Cytochrome P450: Structure, Mechanism and Biochemistry. Carried out with NADPH as the electron donor Plenum Press, New York, NY. and cytochrome c as the artificial electron 11. Guengerich, F.P. (ed.) (1987). Mammalian acceptor by the method of Philips & Langdon^"*^ Cytochromes P450, Vols 1 & 2, CRC Press, Boca as detailed245-247 Raton, FL. 12. Schenkman, J.B. and D. Kupfer (eds) (1982). Using the AA^^Q^Jmin and an EmM~^cm~^ Hepatic Cytochrome P450 Monooxygenase System. = 21 determine [AA55Qjjjjj/min]/0.021 = X nmol Pergamon Press, Elmsford, NY. cytochrome c reduced/min^"^^"^"^^. 13. Ortiz de Montellano, PR. (ed.) (1995). Cytochrome Purified liver P450 reductase preparations P450: Structure, Mechanism and Biochemistry. range from 40-70 ixmol c3^oclirome c reduced/ Plenum Press, New York, NY. mg protein/min. Molar concentrations of purified 14. Waxman, D.J. (1986). Rat hepatic cytochrome P450 reductase are estimated using either a P-450: Comparative study of multiple isozymic molecular weight of 74kDa (based on cDNA forms. In PR. Ortiz de Montellano (ed.). Cytochrome P-450. Structure, Mechanism, and Biochemistry. sequence as well as flavin and protein content) Plenum Press, New York, NY, pp. 525-538. or an apparent molecular weight of 79.5 kDa 15. Gonzalez, F.J. (1989). The molecular biology of (SDS-PAGE). cytochrome P450s. Pharmacol. Rev. 40, 243-288. 16. Guengerich, F.P. (2002). Update information on Aclcnowledgments human P450s. Drug Metab. Rev. 34, 7-15. 17. Wrighton, S.A., M. VandenBranden, J.C. Stevens, L.A. Shipley, and B.J. Ring (1993). In vitro methods Supported by NIH grants DK26506 and for assessing human hepatic drug metabolism: Their GM44037. use in drug development. Drug Metab. Rev. 25, 453^84. 18. Newton, D.J., R.W. Wang, and A.Y Lu (1995). References Cytochrome P450 inhibitors. Evaluation of speci­ ficities in the in vitro metabolism of therapeutic 1. Sato, R. and T. Omura (eds) (1978). Cytochrome agents by human liver microsomes, Drug Metab. P450. Academic Press, New York, NY. Dispos. 23, 154-158. 648 M.A. Correia

19. Nelson, D.R., L. Koymans, T. Kamataki, probes for human cytochromes P450 lAl and 1A2. J.J. Stegeman, R. Feyereisen, D.J. Waxman et al. J. Pharmacol. Exp. Ther 265, 401-407. (1996). P450 superfamily: Update on new 31. Sesardic, D, A. Boobis, B. Murray, S. Murray, sequences, gene mapping, accession numbers and J. Segura, R. De La Torre et al. (1990). Furafylline is nomenclature. Pharmacogenetics 6, \-A2. a potent and selective inhibitor of cytochrome P450 20. Guengerich, F.R (1995). Human cytochrome P450 1A2 in man. Br J. Clin. Pharmacol. 29, 651-663. enzymes. In RR. Ortiz de Montellano (ed.), 32. Kunze, K.L. and W.F Trager (1993). Isoform- Cytochrome P450: Structure, Mechanism and selective mechanism-based inhibition of human Biochemistry. Plenum Press, New York, NY, cytochrome P450 1A2 by fiirafylline. Chem. Res. pp. 473-574. Toxicol. 6, 649-656. 21. Guengerich, F.R (2004). Human cytochrome P450 33. Clarke, S.E., A.D. Ayrton, and R.J. Chenery (1994). enzymes. In, PR. Ortiz de Montellano (ed.). Cyto­ Characterization of the inhibition of P4501A2 by chrome P450: Structure, Mechanism and Bio­ furafylline. Xenobiotica 24, 517-526. chemistry. Plenum Press, New York, NY, pp. 370-530. 34. Tjia, J.R, J. Colbert, and D.J. Back (1996). 22. Rendic, S. and RJ. Di Carlo (1997). Human Theophylline metabolism in human liver micro­ C5^ochrome P450 enzymes: A status report summa­ somes: Inhibition studies. J. Pharmacol. Exp. Ther rizing their reactions, substrates, inducers, and 276,912-917. inhibitors. Drug Metab. Rev. 29, 413-580. 35. Butler, M.N., M. Iwasaki, F.R Guengerich, and 23. Rendic, S. (2002). Summary of information on F.K. Kadlubar (1989). Human cytochrome human CYP enzymes: Human P450 metabolism P-450PIA (P450IA2), the phenacetin 0-deethylase, data. Drug Metab. Rev. 34, 83-448. is primarily responsible for the hepatic 3- 24. Kobayashi, K., K. Urashima, N. Shimada, and demethylation of caffeine and N-oxidation of car­ K. Chiba (2003). Selectivities of human cytochrome cinogenic arylamines, Proc. Natl. Acad. Sci. USA, P450 inhibitors toward rat P450 isoforms: Study 86, 7696-7700. with cDNA-expressed systems of the rat. Drug 36. Yun, C.H., G.R Miller, and FP Guengerich (2000). Metab. Dispos. 31, 833-836. Rate-determining steps in phenacetin oxidations by 25. Kobayashi, K., K. Urashima, N. Shimada, and human cytochrome P450 1A2 and selected K. Chiba (2002). Substrate specificity for rat mutants. Biochemistry 39, 11319-11329. cytochrome P450 (CYP) isoforms: Screening with 37. Yang, TJ., Y Sai, K.W. Krausz, FJ. Gonzalez, and cDNA-expressed systems of the rat. Biochem. H.V Gelboin (1998). Inhibitory monoclonal Pharmacol 63, 889-896. antibodies to human cytochrome P450 1A2: 26. Yuan, R., S. Madani, X.X. Wei, K. Reynolds, and Analysis of phenacetin 0-deethylation in human S.M. Huang (2002). Evaluation of cytochrome P450 liver. Pharmacogenetics 8, 375-382. probe substrates commonly used by the 38. Zhai, S., R. Dai, FK. Friedman, and R.E. Vestal pharmaceutical industry to study in vitro drug inter­ (1998). Comparative inhibition of human actions. Drug Metab. Dispos. 30, 1311-1319. cytochrome P450 lAl and 1A2 by flavonoids. 27. Eagling, VA., J.R Tjia, and D.J. Back (1998). Drug Metab. Dispos. 26, 989-992. Differential selectivity of cytochrome P450 inhi­ 39. Lee, H., H. Yeom, YG. Kim, C.N. Yoon, C. Jin, bitors against probe substrates in human and rat J.S. Choi et al. (1998). Structure-related inhibition liver microsomes. Br J. Clin. Pharmacol. 45, of human hepatic caffeine N3-demethylation by 107-114. naturally occurring flavonoids. Biochem. Pharmacol. 28. Fuhr, U, J. Doehmer, N. Battula, C. Wolfel, 55, 1369-1375. C. Kudla, Y. Keita et al. (1992). Biotransformation 40. Burke, M.D., S. Thompson, R.J. Weaver, C.R. Wolf, of caffeine and theophylline in mammalian cell and R.T. Mayer (1994). Cytochrome P450 speci­ lines genetically engineered for expression of single ficities of alkoxyresorufin 0-dealkylation in human cytochrome P450 isoforms. Biochem. Pharmacol. and rat liver. Biochem. Pharmacol. 48, 923-936. 43, 225-235. 41. Rodrigues, A.D. and R.A. Prough (1992). Induction 29. Tassaneeyakul, W., Z. Mohamed, D.J. Birkett, M.E. of cytochromes P450IA1 and P450IA2 and McManus, M.E. Verones, R.H. Tukey et al. (1992). measurement of catalytic activities. Meth. Enzymol. Caffeine as a probe for human cytochromes P450: 206,423^31. Validation using cDNA expression, immuno- 43. Yun, C.H., T Shimada, and FR Guengerich (1991). inhibition and microsomal kinetic and inhibitor Purification and characterization of human liver techniques. Pharmacogenetics 2, 173-183. microsomal cytochrome P-450 2A6. Mol. 30. Tassaneeyakul, W., D.J. Birkett, M.E. Veronese, Pharmacol. 40, 679-685. M.E. McManus, R.H. Tukey, L.C. Quattrochi et al. 44. Yamano, S., J. Tatsuno, and FJ. Gonzalez (1990). (1993). Specificity of substrate and inhibitor The CYP2A3 gene product catalyzes coumarin Human and Rat Liver Cytochromes P450 649

7-hydroxylation in human liver microsomes. marker of human cytochrome P450 2B6 catalytic Biochemistry 19, 1322-1329. activity. Drug Metab. Dispos. 28, 1222-1230. 45. Sai, Y., T.J. Yang, K.W. Krausz, F.J. Gonzalez, and 57. Richter, T, K. Klein, T.E. Murdter, M. Eichelbaum, H.V Gelboin (1999). An inhibitory monoclonal M. Schwab, and U.M. Zanger (2003). Clopidogrel antibody to human cytochrome P450 2A6 defines and ticlopidine are specific mechanism-based its role in the metabolism of coumarin, 7- inhibitors of human cytochrome P450 2B6. In ethoxycoumarin and 4-nitroanisole in human liver. Proceedings of the 13th International Conference Pharmacogenetics 9, 229-237. on Cytochromes P450. Prague, Czech Republic, 46. Zhang, W., T. Kilicarslan, R.F. Tyndale, and p. S119. E.M. Sellers (2001). Evaluation of methoxsalen, 58. Dai, D., D.C. Zeldin, J.A. Blaisdell, B. Chanas, tranylcypromine, and trj^tamine as specific and S.J. Coulter, B.I. Ghanayem et al. (2001). Poly­ selective CYP2A6 inhibitors in vitro. Drug Metab. morphisms in human CYP2C8 decrease metabo­ Dispos. 29, 897-902 lism of the anticancer drug paclitaxel and arachidonic 47. Taavitsainen, P., R. Juvonen, and O. Pelkonen acid, Pharmacogenetics 11, 597-607. (2001). In vitro inhibition of cytochrome P450 59. Harris, J.W, A. Rahman, B.R. Kim, F.P enzymes in human liver microsomes by a potent Guengerich, and J. Collins (1994). Metabolism of CYP2A6 inhibitor, trans-2-phenylcyclopropylamine taxol by human hepatic microsomes and human (Tranylcypromine), and its nonamine analog, liver slices: Participation of cytochrome P450 3A4 cyclopropylbenzene. Drug Metab. Dispos. 29, and an unknown P450 enzyme. Cancer Res. 54, 217-222. 4026-4035. 48. Draper, A.J., A. Madan, and A. Parkinson (1997). 60. Rahman, A., K.R. Korzekwa, J. Grogan, F.J. Inhibition of coumarin 7-hydroxylase activity in Gonzalez, and J.W. Harris (1994). Selective bio­ human liver microsomes. Arch. Biochem. Biophys. transformation of taxol to 6 alpha-hydroxytaxol by 341,47-61. human cytochrome P450 2C8. Cancer Res. 54, 49. Khojasteh-Bakht, S.C, L.L. Koenigs, R.M. Peter, 5543-5546. W.F. Trager, and S.D. Nelson (1998). (R)-(+)- 61. Wen, X., J.S. Wang, J.T. Backman, J. Laitila, and Menthofuran is a potent, mechanism-based inacti- P.J. Neuvonen (2002). Trimethoprim and sul­ vator of human liver cytochrome P450 2A6. Drug famethoxazole are selective inhibitors of CYP2C8 Metab. Dispos. 26, 701-704. and CYP2C9, respectively. Drug Metab. Dispos. 50. Koenigs, L.L. and W.F. Trager (1998). Mechanism- 30,631-635. based inactivation of P450 2A6 by furano- 62. Wang, J.S. and C.L. DeVane (2003). Involvement of coumarins. Biochemistry 37, 10047-10061. CYP3A4, CYP2C8, and CYP2D6 in the metabolism 51. Heyn, H., R.B. White, and J.C. Stevens (1996). of (R)- and (S)-methadone in vitro. Drug Metab. Catalytic role of cytochrome P450 2B6 in Dispos. 31, 742-747. N-demethylation of ^'-mephenytion. Drug Metab. 63. Tang, W, R.A. Stearns, R.W Wang, S.H. Chiu, and Dispos. 24, 948-954. T.A. Baillie (1999). Roles of human cytochrome 52. Stiborova, M., L. Borek-Dohalska, P. Hodek, P450s 2C9 and 3A4 in the metabolic activation of J. Mraz, and E. Frei (2002). New selective inhibitors diclofenac. Chem. Res. Toxicol. 12, 192-199. of cytochromes P450 2B and their application to 64. Leemann, T., C. Transon, and P. Dayer (1993). antimutagenesis of tamoxifen. Arch. Biochem. Cytochrome P450TB (CYP2C): A major monooxy- Biophys. 403, 41^9. genase catalyzing diclofenac 4'-hydroxylation in 53. Ekins, S., M. VandenBranden, B.J. Ring, and human liver. Life Sci. 52, 29-34. S.A. Wrighton (1997). Examination of purported 65. Rettie, A.E., K.R. Korzekwa, K.L. Kunze, probes of human CYP2B6. Pharmacogenetics 7, R.F. Lawrence, A.C. Eddy, T. Aoyama et al. (1992). 165-179. Hydroxylation of warfarin by human cDNA- 54. Ekins, S. and S.A. Wrighton (1999). The role of expressed cytochrome P-450: A role for P-4502C9 CYP2B6 in human xenobiotic metabolism. Drug in the etiology of (S)-warfarin-drug interactions. Metab. Rev. 31, 719-754. Chem. Res. Toxicol. 5, 54-59. 55. Rae, J.M., N.V Soukhova, D.A. Flockhart, and 66. Giancarlo, G.M., K. Venkatakrishnan, B.W Z. Desta (2002). Triethylenethiophosphoramide is a Granda, L.L. von Moltke, and D.J. Greenblatt specific inhibitor of cytochrome P450 2B6: (2001). Relative contributions of CYP2C9 and Implications for cyclophosphamide metabolism. 2C19 to phenytoin 4-hydroxylation in vitro: Drug Metab. Dispos. 30, 525-530. Inhibition by sulfaphenazole, omeprazole, and 56. Faucette, S.R., R.L. Hawke, E.L. Lecluyse, ticlopidine. Eur J. Clin. Pharmacol. 57, 31-36. S.S. Shord, B. Yan, R.M. Laethem et al. (2000). 67. Relling, M.V, T. Aoyama, F.J. Gonzalez, and Validation of bupropion hydroxylation as a selective U.A. Meyer (1989). Tolbutamide and mephenytoin 650 M.A. Correia

hydroxylation by human cytochrome P450s in the ific substrate of CYP 2C18. Biochemistry 38, CYP2C subfamily. J. Pharmacol. Exp. Then 252, 7828-7836. 442^47. 79. Ha-Duong, N.T., C. Marques-Soares, S. Dijols, 68. Brian, W.R., P.K. Srivastava, D.R. Umbenhauer, M.A. Sari, P.M. Dansette, and D. Mansuy R.S. Lloyd, and F.P. Guengerich (1989). Expression Interaction of new sulfaphenazole derivatives with of a human liver cytochrome P-450 protein with human liver cytochrome P450 2Cs: Structural tolbutamide hydroxylase activity in Saccharomyces determinants required for selective recognition by cerevisiae. Biochemistry 28, 4993-4999. CYP 2C9 and for inhibition of human CYP 2Cs. 69. Srivastava, PK., C.H. Yun, PH. Beaune, C. Ged, Arch. Biochem. Biophys. 394, 189-200. and F.P. Guengerich (1991). Separation of human 80. Wrighton, S.A., J.C. Stevens, G.W. Becker, and liver tolbutamine hydroxylase and f5)-mephenytoin M. VandenBranden (1993). Isolation and character­ 4'-hydroxylase cytochrome P-450 enzymes. Mol. ization of human liver cytochrome P450 2C19: Pharmacol. 40, 69-79. Correlation between 2C19 and S-mephenytoin 4'- 70. Miners, J.O. and D.J. Birkett (1996). Use of tolbu­ hydroxylation. Arch. Biochem. Biophys. 306, tamide as a substrate probe for human hepatic cyto­ 240-245. chrome P450 2C9. Meth. Enzymol. 212, 139-145. 81. Goldstein, J.A., M.B. Faletto, M. Romkes-Sparks, 71. Lasker, J.M., M.R. Wester, E. Aramsombatdee, and T. Sullivan, S. Kitareewan, J.L. Raucy etal. (1994). J.L. Raucy (1998). Characterization of CYP2C19 Evidence that CYP2C19 is the major (S)-mepheny- and CYP2C9 from human liver: Respective roles toin 4'-hydroxylase in humans. Biochemistry 33, in microsomal tolbutamide, S-mephenytoin, and 1743-1752. omeprazole hydroxylation. Arch. Biochem. Biophys. 82. Suzuki, H., M.B. Kneller, R.L. Haining, and 353, 16-24. WF Trager, A.E. Rettie (2002). (+)-N-3-Benzyl- 72. Lopez-Garcia, M.P., P.M. Dansette, and D. Mansuy nirvanol and (-)-N-3-benzyl-phenobarbital: New (1993). Thiophene derivatives as new mechanism- potent and selective in vitro inhibitors of based inhibitors of cytochromes P450: Inactivation CYP2C19. Drug Metab. Dispos. 30, 235-239. of yeast-expressed human liver P450 2C9 by tie- 83. Walsky, R.L. and R.S. Obach (2003). Verification nilic acid. Biochemistry 33, 166-175. of the selectivity of (+)N-3-benzylnirvanol as a 73. Lopez-Garcia, M.P., P.M. Dansette, P. Valadon, CYP2C19 inhibitor. Drug Metab. Dispos. 31, 343. C. Amar, PH. Beaune, F.P Guengerich et al. (1993). 84. Ha-Duong, N.T., S. Dijols, A.C. Macherey, J.A. Human liver P450s expressed in yeast as tools for Goldstein, PM. Dansette, and D. Mansuy (2001). reactive metabolite formation studies: Oxidative Ticlopidine as a selective mechanism-based activation of tienilic acid by P450 2C9 and P450 inhibitor of human cytochrome P450 2C19. 2C10. Eur J. Biochem. 213, 223-232. Biochemistry 4(i, 12112-12122. 74. Shimada, T., K.S. Misono, and F.P. Guengerich 85. Ha-Duong, N.T., S. Dijols, A.C. Macherey, (1986). Human liver microsomal cytochrome PM. Dansette, and D. Mansuy (2001). Inhibition by P-450 mephenytoin 4-hydroxylase, a prototype of ticlopidine and its derivatives of human liver genetic polymorphism in oxidative drug metabo­ cytochrome P450. Mechanism-based inactivation lism. Purification and characterization of two of CYP 2C19 by ticlopidine. Adv. Exp. Med. Biol. similar forms involved in the reaction. J. Biol. 500, 145-148. Chem. 261,909-921. 86. Gonzalez, F.J., T. Matsunaga, K. Nagata, U.A. 75. Kaminsky, L.S. (1989). Warfarin as a probe of Meyer, D.W Nebert, J. Pastewka et al. (1987). cytochromes P450 function. Drug Metab. Rev. 20, Debrisoquine 4-hydroxylase: Characterization of a 479-487. new P450 gene subfamily, regulation, chromoso­ 76. Kaminsky, L.S., M.J. Fasco, and F.P. Guengerich mal mapping, and molecular analysis of the DA rat (1981). Production and apphcation of antibodies to polymorphism. DNA 6, 149-161. rat liver cytochrome P-450. Meth. Enzymol. 74, 87. Gut, J., T. Catin, P Dayer, T. Kronbach, U. Zanger, 262-272. and U.A. Meyer (1986). Debrisoquine/sparteine- 77. Lang, D. and R. Bocker (1995). Highly sensitive type polymorphism of drug oxidation. Purification and specific high-performance liquid chromato­ and characterization of two functionally different graphic analysis of 7-hydroxywarfarin, a marker human liver cytochrome P-450 isozymes involved for human cytochrome P-4502C9 activity. J. in impaired hydroxylation of the prototype Chromatogr Biomed. Appl. 672, 305-309. substrate bufuralol. J. Biol. Chem. 261, 78. Minoletti, C., S. Dijols, RM. Dansette, and 11734-11743. D. Mansuy (1999). Comparison of the substrate 88. Kronbach, T. (1991). Bufuralol, dextromethorphan, specificities of human liver cytochrome P450s 2C9 and debrisoquine as prototype substrates for human and 2C18: Application to the design of a spec­ P450IID6. Meth. Enzymol. 206, 509-517. Human and Rat Liver Cytochromes P450 651

89. Otton, S.V, T. Inaba, and W. Kalow (1984). of cytochrome P450IIE1. Meth. Enzymol. 206, Competitive inhibition of sparteine oxidation in 595-603. human Hver by beta-adrenoceptor antagonists and 101. Tassaneeyakul, W., M.E. Veronese, D.J. Birkett, other cardiovascular drugs. Life Sci. 34, 73-80. EJ. Gonzalez, and J.O. Miners (1993). Validation 90. Bertelsen, K.M., K. Venkatakrishnan, L.L. Von of 4-nitrophenol as an in vitro substrate probe Moltke, R.S. Obach, and D.J. Greenblatt (2003). for human liver CYP2E1 using cDNA expression Apparent mechanism-based inhibition of human and microsomal kinetic techniques. Biochem. CYP2D6 in vitro by paroxetine: Comparison with Pharmacol. 46, 1975-1981. fluoxetine and quinidine. Drug Metab. Dispos. 31, 102. Guengerich, EP, D.H. Kim, and M. Iwasaki 289-293. (1991). Role of human cytochrome P-450 IIEl in 91. Bloomer, J.C, F.R. Woods, R.E. Haddock, the oxidation of many low molecular weight cancer M.S. Lennard, and G.T. Tucker (1992). The role of suspects. Chem. Res. Toxicol. 4, 168-179. cytochrome P4502D6 in the metabolism of parox­ 103. Kharasch, E.D., D.C. Hankins, C. Jubert, K.E. etine by human liver microsomes. Br. J. Clin. Thummel, and J.K. Taraday (1999). Lack of single- Pharmacol. 33, 521-523. dose disulfiram effects on cytochrome P-450 2C9, 92. Sindrup, S.H., K. Brosen, and L.F. Gram (1992). 2C19, 2D6, and 3A4 activities: Evidence for speci­ Pharmacokinetics of the selective serotonin reup­ ficity toward P-450 2E1. Drug Metab. Dispos. 11, take inhibitor paroxetine: Nonlinearity and relation 717-723. to the sparteine oxidation polymorphism. Clin. 104. Chang, TK.H., EJ. Gonzalez, and D.J. Waxman Pharmacol. Ther 51, 288-295. (1994). Evaluation of triacetyloleandomycin, a- 93. Sindrup, S.H., K. Brosen, L.F. Gram, J. Hallas, naphthoflavone and diethyldithiocarbamate as E. Skjelbo, A. Allen et ai (1992). The relationship selective chemical probes for inhibition of human between paroxetine and the sparteine oxidation cytochromes P450. Arch. Biochem. Biophys. 311, polymorphism. Clin. Pharmacol. Ther 51, 437^42. 278-287. 105. Wrighton, S.A., PE. Thomas, D.T. Molowa, 94. Dayer, P, T Leemann, and R. Striberni (1989). M. Haniu, J.E. Shively, S.L. Maines et al. (1986). Dextromethorphan O-demethylation in liver Characterization of ethanol-inducible human liver microsomes as a prototype reaction to monitor N-nitrosodimethylamine demethylase. Biochemistry cytochrome P-450 dbl activity. Clin. Pharmacol. 25,6731-6735. Ther. 45, 34^0. 106. Yoo, J.S., EP Guengerich, and C.S. Yang (1988). 95. Rodrigues, A.D. (1996). Measurement of human Metabolism of N-nitrosodialkylamines by human liver microsomal cytochrome P450 2D6 activity liver microsomes. Cancer Res. 48, 1499-1504. using [O-methyl-^'^Cldextromethorphan as sub­ 107. Yamazaki, H., Y Inui, C.H. Yun, M. Mimura, strate. Meth. Enzymol 111, 186-195. EP. Guengerich, andT. Shimada (1992). Cytochrome 96. Palamanda, J.R., C.N. Casciano, L.A. Norton, P450 2E1 and 2A6 enzymes as major catalysts for R.P Clement, L.V Favreau, C. Lin et ai (2001). metabolic activation of A^-nitrosodialkylamines and Mechanism-based inactivation of CYP2D6 by tobacco-related nitrosamines in human liver micro­ 5-fluoro-2-[4-[(2-phenyl-1 H-imidazol-5-yl) methyl]- somes. Carcinogenesis 13, 1789-1794. l-piperazinyl]pyrimidine. Drug Metab. Dispos. 29, 108. Yamazaki, H., Y. Oda, Y. Funae, S. Imaoka, Y Inui, 863-867. EP Guengerich et al. (1992). Participation of rat 97. Yamazaki, H., Z. Guo, and EP Guengerich (1995). liver cytochrome P450 2E1 in the activation of Selectivity of cytochrome P4502E1 in chlorzoxa­ N-nitrosodimethylamine and N-nitrosodiethyl- zone 6-hydroxylation. Drug Metab. Dispos. 23, amine to products genotoxic in an acetyltrans- 438^40. ferase-overexpressing Salmonella typhimurium 98. Peter, R., R. Bocker, PH. Beaune, M. Iwasaki, EP strain (NM2009). Carcinogenesis 13, 979-985. Guengerich, and C.S. Yang (1990). Hydroxylation 109. Waxman, D.J., C. Attisano, EP Guengerich, and of chlorzoxazone as a specific probe for human liver D.P. Lapenson (1988). Human liver microsomal cytochrome P-450IIE1. Chem. Res. Toxicol. 3, 566- steroid metabolism: Identification of the major 573. Erratum in: Chem. Res. Toxicol. 4, 389, 1991. microsomal steroid hormone 6 beta-hydroxylase 99. Feierman, D.E. and A.L Cederbaum (1986). cytochrome P-450 enzyme. Arch. Biochem. Inhibition of microsomal oxidation of ethanol by Biophys. 263, 424^36. pyrazole and 4-methylpyrazole in vitro. Increased 110. Gillam, E.M., T Baba, B.R. Kim, S. Ohmori, and effectiveness after induction by pyrazole and EP Guengerich (1993). Expression of modified 4-methylpyrazole. Biochem. J. 239, 671-677. human cytochrome P450 3A4 in Escherichia coli 100. Yang, C.S., C.J. Patten, H. Ishizaki, and J.S.H. Yoo and purification and reconstitution of the enzyme. (1992). Induction, purification, and characterization Arch. Biochem. Biophys. 305, 123-131. 652 M.A. Correia

111. Guengerich, F.R (1990). Mechanism-based inacti- 122. Stresser, M.D., M.I. Broudy, S.S. Dehal, vation of human liver cytochrome P-450 IIIA4 by C.J. Patten, and C.L. Crespi (2002). Azamulin is gestodene. Chem. Res. Toxicol. 3, 363-371. superior to ketoconazole as a selective CYP3A 112. Guengerich, F.R, M.V Martin, RH. Beaune, inhibitor probe. Drug Metab. Rev. Abstracts from R Kremers, T. Wolff, and D.J. Waxman (1986). the 11th North American ISSX Meeting, Orlando, Characterization of rat and human liver microso­ FL, USA, Oct. 27-Oct. 31, Vol. 34, Abs. 355, mal cytochrome P-450 forms involved in p. 178. nifedipine oxidation, a prototype for genetic poly­ 123. Jang, G.R., S.A. Wrighton, and L.Z. Benet (1996). morphism in oxidative drug metabolism. J. Biol. Identification of CYP3A4 as the principal enzyme C/zem. 261, 5051-5060. catalyzing mifepristone (RU 486) oxidation in 113. Gonzalez, F.J., B.J. Schmid, M. Umeno, O.W. human liver microsomes. Biochem. Pharmacol. Mcbride, J.R Hardwick, U.A. Meyer et al. (1988). 52,753-761. Human P450RCN1: Sequence, chromosome local­ 124. He, K., T.F Woolf, and RE Hollenberg (1999). ization, and direct evidence through cDNA expres­ Mechanism-based inactivation of cytochrome sion that P450PCN1 is nifedipine oxidase. DMA 7, P-450-3A4 by mifepristone (RU486). J. Pharmacol. 79-86. Exp. Ther 288, 791-797. 114. Guengerich, F.R, W.R. Brian, M. Iwasaki, 125. Khan, K.K., Y.Q. He, M.A. Correia, and M.A. Sari, C. Baarnhielm, and P. Bemtsson J.R. Halpert (2002). Differential oxidation of (1991). Oxidation of dihydropyridine calcium mifepristone by cytochromes P450 3A4 and 3A5: channel blockers and analogues by human liver Selective inactivation of P450 3A4. Drug Metab. cytochrome P-450 IIIA4. J. Med. Chem. 34, Dispos. 30, 985-990. 1838-1844. 126. Jones, D.R., J.C. Gorski, M.A. Hamman, B.S. 115. Varhe, A., M.B. Klaus, T. Olkkola, and Mayhew, S. Rider, and S.D. Hall (1999). Diltiazem P.J. Neuvonen (1994). Oral triazolam is potentially inhibition of cytochrome P-450 3A activity is due hazardous to patients receiving systemic antimy- to metabolite intermediate complex formation. J. cotics. Clin. Pharmacol. Ther. 56, 601-607. Pharmacol. Exp. Ther 290, 1116-1125. 116. Watkins, RB., S.A. Wrighton, R Maurel, 127. Wrighton, S.A., W.R. Brian, M.A. Sari, E.G. Schuetz, G. Mendez-Picon, G.A. Parker et al. M. Iwasaki, F.R Guengerich, J.L. Raucy et al. (1985). Identification of an inducible form of (1990). Studies on the expression and metaboHc cytochrome P-450 in human liver. Proc. Natl. capabilities of human Hver cytochrome P450IIIA5 Acad. Sci. USA 82, 6310-6314. (HLp3). Mol. Pharmacol. 38, 207-213. 117. Watkins, RB., S.A. Murray, L.G. Winkelman, 128. Gillam, E.M., Z. Guo, YE Ueng, H. Yamazaki, D.M. Heuman, S.A. Wrighton, and PS. Guzelian 1. Cock, RE. Reilly et al. (1995). Expression of (1989). Erythromycin breath test as an assay of cytochrome P450 3A5 in Escherichia coli: Effects glucocorticoid-inducible liver cytochromes P-450. of 5' modification, purification, spectral character­ J. Clin. Invest. 83, 688-697. ization, reconstitution conditions, and catalytic 118. Thummel, K.E., C.A. Lee, K.L. Kunze, activities. Arch. Biochem. Biophys. 317, 374-384. S.D. Nelson, and J.T. Slattery (1993). Oxidation of Erratum in: Arch. Biochem. Biophys. 318,498,1995. acetaminophen to N-acetyl-p-aminobenzoquinone 129. Gorski, J.C, S.D. Hall, D.R. Jones, imine by human CYP3A4. Biochem. Pharmacol. M. VandenBranden, and S.A. Wrighton (1994). 45, 1563-1569. Regioselective biotransformation of midazolam by 119. Renaud, J.R, C. Cullin, D. Pompon, R Beaune, and members of the human cytochrome P450 3A D. Mansuy (1990). Expression of human liver (CYP3A) subfamily. Biochem. Pharmacol. 47, cytochrome P450 IIIA4 in yeast. A functional 1643-1653. model for the hepatic enzyme. Eur J. Biochem. 130. Gorski, J.C, D.R. Jones, M.A. Hamman, S.A. 194:889-896. Wrighton, and S.D. Hall (1999). Biotrans­ 120. Kronbach, T., D. Mathys, M. Umeno, formation of alprazolam by members of the human F.J. Gonzalez, and U.A. Meyer (1989). Oxidation cytochrome P4503A subfamily. Xenobiotica 29, of midazolam and triazolam by human liver cyto­ 931-944. chrome P450IIIA4. Mol. Pharmacol. 36, 89-96. 131. Williams, J.A., B.J. Ring, VE. Cantrell, D.R. Jones, 121. Thummel, K.E., D.D. Shen, T.D. PodoU, J. Eckstein, K. Ruterbories et al. (2002). Com­ K.L. Kunze, WE Trager, PS. Hartwell et al. parative metabolic capabilities of CYP3A4, (1994). Use of midazolam as a human cytochrome CYP3A5, and CYP3A7. Drug Metab. Dispos. 30, P450 3A probe: I. In vitro-in vivo correlations in 883-891. liver transplant patients. J. Pharmacol. Exp. Ther 132. Parimoo, B., VM. Mishin, CM. Busch, and 111, 549-556. RE. Thomas (2003). Identification of epitopes on Human and Rat Liver Cytochromes P450 653

cytochrome P450 3A4/5 recognized by mono­ HETE synthesizing enzyme. Br J. Pharmacol. clonal antibodies. Arch. Biochem. Biophys. 414, 133, 325-329. 244-254. 143. Powell, PK., I. Wolf, R. Jin, and J.M. Lasker 133. Kitada, M., T. Kamataki, K. Itahashi, T. Rikihisa, (1998). Metabolism of arachidonic acid to 20- and Y. Kanakubo (1987). P-450 HFLa, a form of hydroxy-5,8,ll,14-eicosatetraenoic acid by P450 cytochrome P-450 purified from human fetal enzymes in human liver: Involvement of CYP4F2 livers, is the 16 alpha-hydroxylase of dehydro- and CYP4A11. J. Pharmacol. Exp. Ther 285, epiandrosterone 3-sulfate. J. Biol. Chem. 161, 1327-1336. 13534-13537. 144. Jin, R., D.R. Koop, J.L. Raucy, and J.M. Asker 134. Nakamura, H., N. Torimoto, I. Ishii, N. Ariyoshi, (1998). Role of human CYP4F2 in hepatic catabo- H. Nakasa, S. Ohmori et al (2003). CYP3A4 and lism of the proinflammatory agent leukotriene B4. CYP3A7-mediated carbamazepine 10,11 -epoxida- Arch. Biochem. Biophys. 359, 89-98. tion are activated by differential endogenous 145. Zhang, X., L. Chen, and J.P Hardwick (2000). Pro­ steroids. Drug Metab. Dispos. 31, 432-^38. moter activity and regulation of the CYP4F2 135. Gillam, E.M., R.M. Wunsch, YE Ueng, T. leukotrieneB(4) omega-hydroxylase gene by per­ Shimada, RE. Reilly, T. Kamataki et al. (1997). oxisomal proliferators and retinoic acid in HepG2 Expression of cytochrome P450 3A7 in cells. Arch. Biochem. Biophys. 378, 364-376. Escherichia coli: Effects of 5' modification and 146. Shak, S. and I. Goldstein (1984). Omega-oxidation catalytic characterization of recombinant enzyme is the major pathway for the catabolism of expressed in bicistronic format with NADPH- leukotriene B4 in human polymorphonuclear cytochrome P450 reductase. Arch. Biochem. iQukocytQS. J. Biol. Chem. 259, 10181-10187. Biophys. 346, 81-90. 147. Bylund, I, M. Bylund, and E.H. Oliw (2001). 136. Kawashima, H., E. Kusunose, Y Kikuta, cDNA cloning and expression of CYP4F12, a H. Kinoshita, S. Tanaka, S. Yamamoto et al. novel human cytochrome P450. Biochem. Biophys. (1994). Purification and cDNA cloning of human Res. Commun. 280, 892-897. liver CYP4A fatty acid co-hydroxylase. J. Biochem. 148. Maeda, Y.R., G. Eggertsen, B. Nyberg, 116,74-80. T. Setoguchi, K.I. Okuda, K. Einarsson et al. 137. Powell, PK., I. Wolf, and J.M. Lasker (1996). (1995). Immunochemical determination of human Identification of CYP4A11 as the major lauric cholesterol 7 alpha-hydroxylase. Eur. J. Biochem. acid omega-hydroxylase in human liver micro­ IIH, 144-148. somes. Arch. Biochem. Biophys. 335, 219-226. 149. Gafvels, M., M. Olin, B.P Chowdhary, 138. Clarke, S.E., S.J. Baldwin, J.C. Bloomer, T. Raudsepp, U. Andersson, B. Persson et al. A.D. Ayrton, R.S. Sozio, and R.J. Chenery (1994). (1999). Structure and chromosomal assignment Lauric acid as a model substrate for the simultaneous of the sterol 12alpha-hydroxylase gene (CYP8B1) determination of cytochrome P450 2E1 and 4A in human and mouse: Eukaryotic cytochrome in hepatic microsomes. Chem. Res. Toxicol. 7, P-450 gene devoid of introns. Genomics 56, 836-842. 184-196. 139. Amet, Y, E Berthou, S. Baird, Y Dreano, J.P Bail, 150. Chun, Y.J., S.Y Ryu, T.C. Jeong, and M.Y Kim and J.E Menez (1995). Validation of the (omega-1)- (2001). Mechanism-based inhibition of human hydroxylation of lauric acid as an in vitro sub­ cytochrome P450 lAl by rhapontigenin. Drug. strate probe for human liver CYP2E1. Biochem. Metab. Dispos. 29, 389-393. Pharmacol. 50, 1775-1782. 151. Guengerich, RP, G.A. Dannan, S.T. Wright, M.V 140. Savas, U, M.H. Hsu, and E.E Johnson (2003). Martin, and L.S. Kaminsky (1982). Purification Differential regulation of human CYP4A genes by and characterization of liver microsomal cyto­ peroxisome proliferators and dexamethasone. chromes P-450: Electrophoretic, spectral, catalytic, Arch. Biochem. Biophys. 409, 212-220. and immunochemical properties and inducibility 141. Oglivie, B.W., S.M. Otradovec, B.L. Paris, of eight isozymes isolated from rats treated with J.A. Scheinkoenig, P.W. Carrott, S.P. Loecker et al. phenobarbital or beta-naphthoflavone. Biochemistry (2000). 10-(imidazolyl)-decanoic acid (10-IDA) is 21, 6019-6030. a selective and potent inhibitor of CYP4A9/11. 152. Sesardic, D., R.J. Edwards, D.S. Davies, PE. Drug. Metab. Rev. Abstracts from the 10th North Thomas, W Levin, and A.R. Boobis (1990). High American ISSX Meeting, Indianapolis, IN, USA, affinity phenacetin O-deethylase is catalysed Vol. 32 (Suppl. 2), Abs. 188, p. 230. specifically by cytochrome P450d (P450IA2) in the 142. Miyata, N., K. Taniguchi, T. Seki, T. Ishimoto, liver of the rat. Biochem. Pharmacol. 39, 489^98. M. Sato-Watanabe, Y Yasuda et al. (2001). 153. Sarkar, M.A. and B.J. Jackson (1994). HET0016, a potent and selective inhibitor of 20- Theophylline N-demethylations as probes for 654 M.A. Correia

P4501A1 and P4501A2. Drug Metab. Dispos. 22, 164. Smith, S.J., K.R. Korzekwa, T. Aoyama, 827-834. F.J. Gonzalez, J.F. Darbyshire, K. Sugiyama et al. 154. Chun, Y.J., S. Kim, D. Kim, S.K. Lee, and (1992). 12 alpha-hydroxytestosterone. A hitherto F.P. Guengerich (2001). A new selective and potent unidentified testosterone metabolite produced by inhibitor of human c3^ochrome P450 IBl and its cytochrome P-450 2A2. Drug Metab. Dispos. 20, application to antimutagenesis. Cancer Res. 61, 566-571. 8164-8170. Erratum in: Cancer Res. 62, 1232, 165. Lunetta, J.M., K. Sugiyama, and M.A. Correia 2002. (1989). Secobarbital-mediated inactivation of rat 155. Shimada, T, H. Yamazaki, M. Foroozesh, liver cytochrome P-450b: A mechanistic reap­ N.E. Hopkins, W.L. Alworth, F.P. Guengerich praisal. Mol. Pharmacol. 35, 10-17. (1998). Selectivity of polycyclic inhibitors for 166. He, K., A.M. Falick, B. Chen, F Nilsson, and M.A. human cytochrome P450s lAl, 1A2, and IBl. Correia (1996). Identification of the heme adduct Chem. Res. Toxicol. 11, 1048-1056. and an active site peptide modified during mecha­ 156. Shimada, T., F. Tsumura, E.M. Gillam, nism-based inactivation of rat liver cytochrome FP Guengerich, and K. Inoue (2000). Roles of P450 2B1 by secobarbital. Chem. Res. Toxicol. 9, NADPH-P450 reductase in the 0-deethylation of 614-622. 7-ethoxycoumarin by recombinant human cyto­ 167. Lubet, R.A., R.T. Mayer, J.W Cameron, R.W. Nims, chrome P4501B1 variants in Escherichia coli. M.D. Burke, T Wolff e/ al (1985). Dealkylation of Protein Expr Purif. 20, 73-80. pentoxyresorufin: A rapid and sensitive assay for 157. Badawi, A.F, E.L. Cavalieri, and E.G. Rogan measuring induction of cytochrome(s) P-450 by (2000). Effect of chlorinated hydrocarbons on phenobarbital and other xenobiotics in the rat. Arch. expression of cytochrome P450 lAl, 1A2 and IBl Biochem. Biophys. 238, 43^8. and 2- and 4-hydroxylation of 17beta-estradiol in 168. Halpert, J., J.Y. Jaw, C. Balfour, and female Sprague-Dawley rats. Carcinogenesis 21, L.S. Kaminsky (1990). Selective inactivation by 1593-1599. chlorofluoroacetamides of the major phenobarbi- 158. Hayes, C.L., D.C. Spink, B.C. Spink, J.Q. Cao, N.J. tal-inducible form(s) of rat liver cytochrome Walker, and T.R. Sutter (1996). 17 beta-estradiol P-450. Drug Metab Dispos. 18, 168-174. hydroxylation catalyzed by human cytochrome 169. Hopkins, N.E., M.K. Foroozesh, and W.L. Alworth P450 IBl. Proc. Natl. Acad. Sci. USA 93, (1992). Suicide inhibitors of cytochrome P450 9776-9781. lAl and P450 2B1. Biochem. Pharmacol. 44, 159. Levin, W, RE. Thomas, D.E. Ryan, and A.W. 787-796. Wood (1987). Isozyme specificity of testosterone 170. Roberts, E.S., N.E. Hopkins, M. Foroozesh, 7a-hydroxylation in rat hepatic microsomes: Is W.L. Alworth, J.R. Halpert, and PF Hollenberg cytochrome P-450a the sole catalyst? Arch. Biochem. et al. (1997). Inactivation of cytochrome P450s Biophys. 258, 630-635. 2B1, 2B4, 2B6, and 2B11 by arylalkynes. Drug 160. Waxman, D.J., A. Ko, and C. Walsh (1983). Metab Dispos. 25, 1242-1248. Regioselectivity and stereoselectivity of androgen 171. Swinney, D.C, D.E. Ryan, RE. Thomas, and hydroxylations catalyzed by cytochrome P-450 W Levin (1987). Regioselective progesterone isozymes purified from phenobarbital-induced rat hydroxylation catalyzed by eleven rat hepatic liver. J. Biol. Chem. 258, 11937-11947. cytochrome P-450 isozymes. Biochemistry 26, 161. Waxman, D.J. (1988). Interactions of hepatic 7073-7083. cytochromes P-450 with steroid hormones. 172. Halpert, J., J.Y. Jaw, and C. Balfour (1989). Regioselectivity and stereoselectivity of steroid Specific inactivation by 17p-substituted steroids metabolism and hormonal regulation of rat P-450 of rabbit and rat liver cytochromes P-450 res­ enzyme expression. Biochem. Pharmacol. 37, ponsible for progesterone 21-hydroxylation. Mol. 71-84. Pharmacol. 34, 148-156. 162. Wood, A.W, D.R. Ryan, RE. Thomas, and 173. Kobayashi, K., K. Urashima, N. Shimada, and W Levin (1983). Regio- and stereoselective K. Chiba (2003). Selectivities of human cyto­ metabolism of two Cjp steroids by five highly puri­ chrome P450 inhibitors toward rat P450 isoforms: fied and reconstituted rat hepatic cytochrome Study with cDNA-expressed systems of the rat. P450 isozymes. J. Biol. Chem. 258, 8839-8847. Drug Metab. Dispos. 31, 833-836. 163. Arlotto, M.P, J.M. Trant, and R.W Estabrook 174. Masubuchi, Y, A. Ose, and T. Horie (2001). (1992). Measurement of steroid hydroxylation Mechanism-based inactivation of CYP2C11 by reactions by high-performance liquid chromatog­ diclofenac. Drug Metab. Dispos. 29, 1190-1195. raphy as indicator of P450 identity and function. 175. Shen, S., S.J. Hargus, B.M. Martin, and L.R. Pohl Meth. Enzymol 206, 454-462. (1997). Cytochrome P4502C11 is a target of Human and Rat Liver Cytochromes P450 655

diclofenac covalent binding in rats. Chem. Res. cytochrome P-450 2E1 by diallyl sulfide and its Toxicol. 10, 420-423. metabolites. Chem. Res. Toxicol. 4, 642-647. 176. MacGeoch, C, E.T. Morgan, J. Halpert, and 187. Jin, L. and TA. BaiUie (1997). Metabohsm of the J.A. Gustafsson (1984). Purification, characteriza­ chemoprotective agent diallyl sulfide to glutathione tion, and pituitary regulation of the sex-specific conjugates in rats. Chem. Res. Toxicol 10, 318-327. cytochrome P-450 15 beta-hydroxylase from liver 188. Premdas, PD., R.J. Bowers, and RG. Forkert microsomes of untreated female rats. J. Biol. (2000). Inactivation of hepatic CYP2E1 by an Chem. 259, 15433-15439. epoxide of diallyl sulfone. J. Pharmacol. Exp. 177. Wan, J., S. Imaoka, T. Chow, T. Hiroi, Y. Yabusaki, Ther 293, 1112-1120. and Y. Funae (1997). Expression of four rat 189. Ishizaki, H., J.F Brady, S.M. Ning, and C.S. Yang CYP2D isoforms in Saccharomyces cerevisiae and (1990). Effect of phenethyl isothiocyanate on micro­ their catalytic specificity. Arch. Biochem. Biophys. somal N-nitrosodimethylamine metabolism and other 348, 383-390. monooxygenase activities. Xenobiotica 20, 255-264. 178. Chow, T., S. Imaoka, T. Hiroi, and Y. Funae (1999). 190. Sonderfan, A.J., M.R Arlotto, D.R. Dutton, Developmental changes in the catalytic activity S.K. McMillen, and A. Parkinson (1987). and expression of CYP2D isoforms in the rat liver. Regulation of testosterone hydroxylation by rat DrugMetab. Dispos. 11, 188-192. liver microsomal cytochrome P-450. Arch. 179. Lin, L.Y., M. Fujimoto, E.W. Distefano, Biochem. Biophys. 255, 27-41. D.A. Schmitz, A. Jayasinghe, and A.K. Cho 191. Underwood, M.C, J.R. Cashman, and M.A. (1996). Selective mechanism-based inactivation Correia (1992). Specifically designed thiosteroids of rat CYP2D by 4-allyloxymethamphetamine. as active site-directed probes for fiinctional dissec­ J. Pharmacol. Exp. Then 111, 595-603. tion of cytochrome P-450 3A isozymes. Chem. 180. Larrey, D., L.M. Distlerath, G.A. Dannan, Res. Toxicol. 5, 42-53. G.R. Wilkinson, and F.R Guengerich (1984). 192. Wrighton, S.A., R Maurel, E.G. Schuetz, Purification and characterization of the rat liver RB. Watkins, B. Young, and RS. Guzehan (1985). microsomal cytochrome P-450 involved in the Identification of the cytochrome P-450 induced by 4-hydroxylation of debrisoquine, a prototype for macrolide antibiotics in rat liver as the glucocorti­ genetic variation in oxidative drug metabolism. coid responsive cytochrome P-450p. Biochemistry Biochemistry 23, 2787-2795. 24,2171-2178. 181. Tanaka, E. (2001). Chlorzoxazone: A probe drug the 193. Watkins, RB., S.A. Wrighton, E.G. Schuetz, metabolism of which can be used to monitor R Maurel, and RS. Guzelian (1986). Macrolide one-point blood sampling in the carbon tetrachloride- antibiotics inhibit the degradation of the glucocor- intoxicated rat. Hum. Exp. Toxicol. 20, 381-385. ticoid-responsive cytochrome P-450p in rat hepa- 182. Mizuno, D., E. Tanaka, K. Tanno, and S. Misawa tocytes in vivo and in primary monolayer culture. (2000). Chlorzoxazone: A probe drug whose J. Biol. Chem. 261, 6264-6271. metabolism can be used to monitor toluene 194. Wang, H., K.L. NapoH, and H.W. Strobel (2000). exposure in rats. Arch. Toxicol. 74, 139-144. Cytochrome P450 3A9 catalyzes the metabolism 183. Mathews, J.M., A.S. Etheridge, J.H. Raymer, S.R. of progesterone and other steroid hormones. Mol Black, D.W Pulliam Jr., and J.R. Bucher (1998). Cell. Biochem. 213, 127-135. Selective inhibition of cytochrome P450 2E1 in 195. Xue, L., V.G. Zgoda, B. Arison, and M.A. Correia vivo and in vitro with trans-1,2-dichloroethylene. (2003). Rat liver CYP3A9: Structure-function rela­ Chem. Res. Toxicol. 11, 778-785. tionships to its human liver orthologs: Site-directed 184. Yoo, J.S., T.J. Smith, S.M. King, M.J. Lee, mutagenesis to an efficient progesterone dihydrox- RE. Thomas, and C.S. Yang (1992). Modulation of ylase. Arch. Biochem. Biophys. 409, 113-126. the levels of cytochromes P450 in rat liver and 196. Gibson, G.G., T.C. Orton, and RR Tamburini lung by dietary lipid. Biochem. Pharmacol. 43, (1982). Cytochrome P-450 induction by clofibrate: 2535-2542. Purification and properties of a hepatic cyto­ 185. Yamazaki, H., Y. Oda, Y Funae, S. Imaoka, Y Inui, chrome P-450 relatively specific for the 12- and F.P. Guengerich et al. (1992). Participation of rat 11-hydroxylation of dodecanoic acid (lauric acid). liver cytochrome P450 2E1 in the activation of Biochem. J. 203, 161-168. N-nitrosodimethylamine and N-nitrosodiethyl- 197. CaJacob, C.A., WK. Chan, E. Shepard, and amine to products genotoxic in an acetyltrans- RR. Ortiz de Montellano (1988). The catalytic site ferase-overexpressing Salmonella typhimurium of rat hepatic lauric acid omega-hydroxylase. strain (NM2009). Carcinogenesis 13, 979-985. Protein versus prosthetic heme alkylation in the 186. Brady, J.F., H. Ishizaki, J.M. Fukuto, M.C. Lin, omega-hydroxylation of acetylenic fatty acids. J. A. Fadel, J.M. Gapac et al. (1991). Inhibition of Biol. Chem. 263, 18640-18649. 656 M.A. Correia

198. Ortiz de Montellano, P.R. and N.O. Reich (1984). in male Sprague-Dawley rats. Fundam. Appl. Specific inactivation of hepatic fatty acid hydrox­ Toxicol. 19, 43-49. ylases by acetylenic fatty acids. J. Biol. Chem. 259, 210. Levine, M. and G.D. Bellward (1995). Effect of 4136-4141. cimetidine on hepatic cytochrome P450: Evidence 199. Chiang, J.Y. (1991). Reversed-phase high- for formation of a metabolite-intermediate com­ performance liquid chromatography assay of plex. DrugMetab. Dispos. 23, 1407-1411. cholesterol 7 alpha-hydroxylase. Meth. Enzymol. 211. Levine, M., E.Y. Law, S.M. Bandiera, T.K. Chang, 206,483-491. and G.D. Bellward (1998). In vivo cimetidine 200. Raucy, J.L., J.M. Lasker, C.S. Lieber, and M. Black inhibits hepatic CYP2C6 and CYP2C11 but not (1989). Acetaminophen activation by human liver CYPlAl in adult male rats. J. Pharmacol. Exp. cytochromes P450nEl and P450IA2. Arch. Then 284, 493-499. Biochem. Biophys. Ill, 270-283. 212. Gerber, M.C, G.A. Tejwani, N. Gerber, and J.R. 201. Sinclair, J., E. JefFery, S. Wrighton, V Kostrubsky, Bianchine (1985). Drug interactions with cimeti­ J. Szakacs, S. Wood, and R Sinclair (1998). dine: An update. Pharmacol. Ther 11, 353-370. Alcohol-mediated increases in acetaminophen 213. Smith, S.R. and M.J. Kendall (1988). Ranitidine hepatotoxicity: role of CYP2E and CYP3A. versus cimetidine. A comparison of their potential Biochem. Pharmacol. 55, 1557-1565. to cause clinically important drug interactions. 202. Imaoka, S., K. Inoue, and Y. Funae (1988). Clin. Pharmacokinet. 15, 44-56. Aminopyrine metabolism by multiple forms of 214. Correia, M.A., C. Decker, K. Sugiyama, P Caldera, cytochrome P-450 from rat liver microsomes: L. Bornheim, S.A. Wrighton et al. (1987). Simultaneous quantitation of four aminopyrine Degradation of rat hepatic cj^ochrome P-450 metabolites by high-performance liquid chromatog­ heme by 3,5-dicarbethoxy-2,6-dimethyl-4- raphy. Arch. Biochem. Biophys. 265, 159-170. ethyl-l,4-dihydropyridine to irreversibly bound 203. Bornheim, L.M., M.C. Underwood, P. Caldera, protein adducts. Arch. Biochem. Biophys. 258, A.E. Rettie, W.E Trager, S.A. Wrighton et al. 436-451. (1987). Inactivation of multiple hepatic cj^o- 215. Lesca, P., E. Rafidinarivo, P. LeCointe, and chrome P-450 isozymes in rats by allyhsopropy- D. Mansuy (1979). A class of strong inhibitors of lacetamide: Mechanistic implications. Mol. microsomal monooxygenases: The ellipticines. Pharmacol. 32, 299-308. Chem. Biol. Interact. 24, 189-198. 204. Nebert, D.W (1982). Genetic differences in 216. Tassaneeyakul, W, D.J. Birkett, M.E. Veronese, the induction of monooxygenase activities by M.E. McManus, R.H. Tukey, L.C. Quattrochi et al. polycyclic aromatic compounds. In J.B. (1993). Specificity of substrate and inhibitor Schenkman and D. Kupfer (eds). Hepatic probes for human cytochromes P450 lAl and Cytochrome P-450 Monooxygenase System. 1A2. J. Pharmacol. Exp. Ther 265, 401^07. Pergamon Press, New York, NY, pp. 269-291. 217. Hemeryck, A. and FM. Belpaire (2002). Selective 205. Prough, R.A., M.D. Burke, and R.T. Mayer (1978). serotonin reuptake inhibitors and cytochrome Direct fluorometric methods for measuring mixed- P-450 mediated drug-drug interactions: An update. fiinction oxidase activity. Meth. Enzymol. 52, Curr Drug. Metab. 3, 13-37. 372-377. 218. Richelson, E. (1997). Pharmacokinetic drug inter­ 206. Correia, M.A. and G.J. Mannering (1973). Reduced actions of new antidepressants: A review of the diphosphopyridine nucleotide synergism of the effects on the metabolism of other drugs. Mayo reduced triphosphopyridine nucleotide dependent Clin. Proc. 72, 835-847. mixed function oxidase of hepatic microsomes. 219. Letteron, P., V Descatoire, D. Larrey, M. Tinel, Role of the Type I drug binding site of cytochrome J. Geneve, and D. Pessayre (1986). Inactivation and P-450. Mol. Pharmacol. 9, 470-485. induction of cytochrome P-450 by various pso­ 207. Ortiz de Montellano, PR. and A.K. Costa (1986). ralen derivatives in rats. J. Pharmacol. Exp. Ther Dissociation of cytochrome P-450 inactivation 238, 685-692. and induction. Arch. Biochem. Biophys. 251, 220. Koenigs, L.L. and WF Trager (1998). Mechanism- 514-524. based inactivation of cytochrome P450 2B1 by 208. Mico, B.A., D.A. Federowicz, M.G. Ripple, and 8-methoxypsoralen and several other furano- W. Kerns (1988). In vivo inhibition of oxidative coumarins. Biochemistry 37, 13184-13193. drug metabolism by, and acute toxicity of 221. Testa, B. and P Jenner (1981). Inhibitors of 1-aminobenzotriazole (ABT). Biochem. Pharmacol. cytochrome P-450s and their mechanism of action. 37,2515-2519. DrugMetab. Rev. 12, 1-117. 209. Mugford, C.A., M. Mortillo, B.A. Mico, and J.B. 222. Waxman, D.J. and C. Walsh (1983). Cytochrome Tarloff (1992). 1-Aminobenzotriazole-induced P-450 isozyme 1 from phenobarbital-induced destruction of hepatic and renal cytochromes P450 rat liver: Purification, characterization, and Human and Rat Liver Cytochromes P450 657

interactions with metyrapone and cytochrome b5. 235. Philpot, R.M. and E. Hodgson (1972). The effect Biochemistry 22, 4846-4855. of piperonyl butoxide concentration on the forma­ 223. Franklin, M.R. (1972). Inhibition of hepatic oxida­ tion of cytochrome P-450 difference spectra in tive xenobiotic metabolism by piperonyl butoxide. hepatic microsomes from mice. Mol. Pharmacol. Biochem. Pharmacol. 21, 3287-3299. 8, 204-214. 224. Hodgson, E. and R.M. Philpot (1974). Interaction 236. Franklin, M.R. (1977). Inhibition of mixed-fiinc- of methylenedioxyphenyl (1,3-benzodioxole) com­ tion oxidations by substrates forming reduced pounds with enzymes and their effects on mam­ cytochrome P-450 metabolic-intermediate com­ mals. Drug. Metab. Rev. 3, 231-301. plexes. Pharmacol. Ther. A. 2, 227-245. 225. Buening, M.K. and Franklin, M.R. (1974). The 237. Franklin, M.R. (1991). Cytochrome P450 meta­ formation of complexes absorbing at 455 nm from bolic intermediate complexes from macrolide cytochrome P-450 and metabolites of compounds antibiotics and related compounds. Meth. Enzymol. related to SKF 525-A. Drug Metab. Dispos. 2, 206,559-573. 386-390. 238. Larrey, D., M. Tinel, and D. Pessayre (1983). 226. Omura, T. and R. Sato (1964). The carbon monox­ Formation of inactive cytochrome P-450 ide-binding pigment of liver microsomes. I. Fe(II)-metabolite complexes with several erythro­ Evidence for its hemoprotein nature. J. Biol. Chem. mycin derivatives but not with josamycin and 239, 2370-2378. midecamycin in rats. Biochem. Pharmacol. 32, 227. Estabrook, R.W., J.A. Peterson, J. Baron, and A.G. 1487-1493. Hildebrandt (1972). The spectrophotometric 239. Delaforge, M., E. Sartori, and D. Mansuy (1988). measurement of turbid suspensions of cytochromes In vivo and in vitro effects of a new macrolide associated with drug metabolism. In C.F. Chignell antibiotic roxithromycin on rat liver cyto­ (ed.). Methods in Pharmacology, Vol. 2. Appleton- chrome P-450: Comparison with troleandomycin Century-Crofts, New York, NY, pp. 303-350. and erythromycin. Chem. Biol. Interact. 68, 228. Matsubara, T, M. Koike, A. Touchi, Y. Tochino, 179-188. and K. Sugeno (1976). Quantitative determination 240. Paul, K.G., H. Theorell, and A. Akeson (1953). The of cytochrome P-450 in rat liver homogenate. molar light absorption of pyridine ferroprotopor- Anal. Biochem. 75, 596-603. phyrin (Pyridine Haemochromogen). Acta. Chem. 229. Ryan, D.E., RE. Thomas, D. Korzeniowski, and Scand. 7, 1284-1287. W. Levin (1979). Separation and characterization 241. Waterman, M.R. (1978). Spectral characterization of highly purified forms of liver microsomal of human hemoglobin and its derivatives. Meth. cytochrome P-450 from rats treated with poly chlo­ Enzymol. 52, 456-463. rinated biphenyls, phenobarbital, and 3-methyl- 242. Klingenberg, M. (1958). Pigments of rat liver cholanthrene. J 5?o/. Chem. 254, 1365-1374. microsomes, ^rc/?. Biochem. Biophys. 75, 376-386. 230. Ryan, D.E., S. lida, A.W. Wood, RE. Thomas, 243. Strittmatter, P (1960). The nature of the heme C.S. Lieber, and W. Levin (1984). Characterization binding in microsomal cytochrome b5. J. Biol. of three highly purified cytochromes P-450 from Chem. 235, 2492-2497. hepatic microsomes of adult male rats. J. Biol. 244. Strittmatter, P, P Fleming, M. Connors, and Chem. 259, 1239-1250. D. Corcoran (1978). Purification of cytochrome b3. 231. Ryan, D.E., RE. Thomas, and W. Levin (1980). Meth. Enzymol. 52, 97-101. Hepatic microsomal cytochrome P-450 from rats 245. Guengerich, F.P. (1994). Analysis and characteriza­ treated with isosafrole. Purification and character­ tion of enzymes. In A.W. Hayes (ed.). Principles ization of four enzymic forms. J. Biol. Chem. 255, and Methods of Toxicology. Raven Press, Ltd., 7941-7955. New York, NY. pp. 1259-1313. 232. Jefcoate, C.R. (1978). Measurement of substrate 246. Phillips, A.H. and R.G. Langdon (1962). Hepatic and inhibitor binding to microsomal cytochrome triphosphopyridine nucleotide-cytochrome c reduc­ P-450 by optical-difference spectroscopy. Meth. tase: Isolation, characterization, and kinetic studies. Enzymol 52, 258-279. J. Biol. Chem. 237, 2652-2660. 233. Omura, T. and R. Sato (1964). The carbon monox­ 247. Strobel, H.W and J.D. Dignam (1978). ide-binding pigment of liver microsomes. II. Purification and properties of NADPH- Solubilization, purification, and properties. J. Biol. cytochrome P-450 reductase. Meth. Enzymol. 52, Chem. 239, 2379-2385. 89-96. 234. Elcombe, C.R., J. Bridges, R.H. Nimmo-Smith, and 248. Wang, H., R. Dick, H. Yin, E. Licad-Coles, D. J. Werringloer (1975). Cumene hydroperoxide- Kroetz, G. Szklarz et al (1998). Structure-function mediated formation of inhibited complexes of relationships of human liver cytochromes P450 3 A: methylenedioxyphenyl compounds with cytochrome Aflatoxin Bl metabolism as a probe. Biochemistry P450. Biochem. Soc. Trans. 3, 967-970. 37, 12536-12545. Index

Abiraterone, 292 AflatoxinGl,384 Absorption anisotropy, 93 Age effects on P450, 347, 350, 536, 537 ABT, see 1-Aminobenzotriazole Agrobacterium tumafaciens, 589 Acenocoumarol, 411 Ah receptor. See Aryl hydrocarbon receptor Acetaldehyde, 28-30, 419 Ah responsive elements, 338 Abscisic acid, 259 AIA, see 2-lsopropyl-4-pentenamide 9'-propargyl-, 259 Aldehyde, as a product, 75 Acetaminophen, 119, 211, 331, 394, 395, 399, 422, 638 Aldehyde oxidation of cooperativity in interaction, 429 to carboxylic acids, 217, 221, 284, 419 Acetanilide, 632 CO2 loss, 222 Acetone, 419 via deformylation, 221, 222, 284 Acetonitrile, 409 isoform specificity, 221 4-Acetoxyandrost-4-ene-3,17-dione, 289 P450 inactivation, 222, 282, 284 Acetylenes, oxidation of ALDH3A1,338 inactivation of P450, 200, 256, 269, 270 Aldosterone biosynthesis, 135, 292 mechanism, 198 Aldosteronism, P450 link to, 383 metaboHsm of, 198, 200, 270 Alkaloids, 553-555, 557, 571, 572 oxirene, 258 AlkB, 15 rearrangement during, 198, 270, 271 N-Alkylprotoporphyrin IX, see Heme Acidovorax avenue, 568 see Protoporphyrin IX Acrylonitrile, 384, 420 Allelochemicals, 553 ACTH, 445, 446, 453 Allene oxide synthase, 158, 555 Activating transcription factor-1 (ATF-1), 446,447 AUenes, 283, 289 Activating transcription factor-2 (ATF-2), 446, 447 Allobarbital, 256 Active site, see P450 Allylisopropylacetamide, see 2-Isopropyl-4- Acyl CoA, 322 pentenamide Ad4 Binding protein. See Steroidogenic Factor 1 4-Allyloxymethamphetamine, 636 Adamantane, 28, 31,32 Alprazolam, 622, 630 perdeuterated, 64 Alzheimer's disease, 461 Addison's disease, 446, 450 Amides AdE element, 445 oxidation potential, 197 Adenosine 2',5'-diphosphate, 127, 128 isotope effect, 197 Adrenal hyperplasia, P450 link, 383,446-448, 453 Amine oxidation, 193 Adrenarche, 450 4-Aminoandrostan-1,4,6-triene-3,17-dione, 289 Adrenodoxin, 116, 134, 454 2-Aminoanthracene, 401, 436 interaction with adrenodoxin reductase, 98, 134, 137 O-Aminoazotoluene, 401 interaction with P450, 135, 137, 419, 445 1-Aminobenzotriazole, 275, 276, 294, 641 maturation, 135 N-benzyl-, 275 structure of, 97, 99, 136, 137 N-(a-methylbenzyl)-, 275 Adrenodoxin reductase, 116, 134, 454 N-(a-ethylbenzyl)-, 275 structure of, 97, 99, 136, 137 4-(4'-Aminobenzyl)-2-oxazolidinones, 288 Adriamycin, 598 4-Aminobiphenyl, 384, 401 AF-1,323 (22/?)-22-Aminocholesterol, 286 AF-2, 333 6-Aminochrysene, 384,401 AFK108,291 -l,2-diol,401 AflatoxinBj, 211,629 2-Aminofluorene, 384, 401, 436 biosynthesis, 224, 225, 603 Aminoglutethimide, 250, 287, 445, 452 oxidation of, 384, 409, 423, 425, 431-433 pyridyl-, 250, 287 enhancement by aNF, 427, 428 2-Amino-6-methyldipyrido[l,2-a:3,2'-

659 660 Index

2-Amino-3-methylimidazo[4,5-/|quinoline, 384 Antibodies contd. 2-Amino-1 -methyl-6-phenylimidazo-[4,5-Z>]pyridine, 384 autoantibodies, 262, 275,410,418,422,443,446,450 3-Amino-1 -methyl-5i/-pyrido[4,3-Z7]indole, 384 inhibition of activities, 390-392 l-Aminopyrene, 401 phage display library, 390 Aminopyrine, 638 selectivity, 390, 405 1 -Amino-2,2,6,6-tetramethylpiperidine, 267 to quantitate P450, 251, 390-392 3-Amino-1,2,4-triazole, 280, 421 Antifungal agents, 585-587, 592, 593, 598, 603, Amiodarone, 407, 430 604,607 Ammi majus, 223 Antipyrine, 398, 399 Amodiaquine, 407 Antisense, 543 Amphetamine, 285 ttj-Antitrypsin, 443 Amphotericin B, 593, 598-600, 606 AP-1,446,459 Amycolatopsis mediterranei, 595 AP-2, 442, 445 Amycolatopsis orientalis, 106 Apium graveolans (celery), 553 Anastrozole, 287, 288 Apoptosis, 116 Androgen oxidation Aprobarbital, 256 aromatization, 379 ARA9, 336, 337 hormonal effects on P450, 350 Arabidopsis thaliana, 225, 259, 554, 555, 558, 560 2a-hydroxylation, 348 CY51 phylogenetic tree, 591 16a-hydroxylation, 348 CYP61, absence of, 592 Androgens gene absence in, 556, 568 depletion by cisplatin, 362, 363 host for foreign pathways, 562, 564, 566, 571, 573, 574 hormonal effects, 350 Arachidonic acid imprinting, 349 binding to P450, effects, 132 Androstane receptor (CAR), 323, 326, 327, 406,424 in disease pathophysiology, 531 ligands,328,331 in glycerophospholipids, 535, 541 nuclear translocation, 330 metabolism of, 292, 378, 408, 535-537 nullmice, 330, 331 hydroxylation, 379, 434, 436, 437, 595, 596, phosphorylation, 329, 331 621,631 role, 405, 408 epoxidation, 423, 531, 539-541, 545 subcellular localization, 329 physiological roles of metabolites, 535, 538, 543-545 5a-Androstane-3a,17p-diol, 3,17-disulfate, 635 PPAR Hgand, 332 Androstanedione, 452 L-Arginine, 16 Androst-1,4-diene-3,17-dione N-hydroxy-, 16 1-methyl-, 289 5-e/7/-Aristone, 569 Androst-4-ene-3,17-dione ARNT, 336, 338, 397 as substrate, 638 Aromatase, see CYP19A1 in sterol biosynthesis, 217,218 Aromatic rings, oxidation of Androst-5-ene-7,l 7-dione, 289 ipso substitution, 76, 185, 203, 204, 207 5,16-Androstadiene-3 p-ol, 449 isotope effects, 202, 203 1,4,6-Androstatriene-3,17-dione, 289 mechanism, 75, 76 Angiotensin II, 541 •^O studies, 204 Aniline, 639 Arrhythmia, 394 aromatic oxidation, 204 Aryl hydrocarbon receptor, 323, 324, 335 as substrate, 638, 646 Ah locus, 395 N,N-Dimethyl- Ah responsive, 400 N-demethylation, 405 allelic variations, 395, 397 N-oxidation of, 185, 194 see ARNT isotope effects on, 194-196 see Hsp90 nitrogen radical cation pK^, 195 ligands, 335-337 oxidation potential, 195 mechanism of action, 337, 338 Anisoles, 204 negative P450 regulation, 363 Anthocyanidins, 570 null mice, 338 Anthracene, 363 photoaffinity labeling, 335 Antibodies repressor protein, 338 antipeptide, 390 Aryl migration in P450 reaction, 227, 554, 569 Index 661

Ascorbic acid, 23, 282 Benzo[a]pyrene contd. Aspergillus 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, 384, fumigatus, 591, 602, 603, 608 395,401 nidulans, 586, 587 4,5-diol, 401 niger, 603 DNA adducts, 207 ochmceous, 586 6-fluoro-, 208 parasiticus, 224 3-hydroxylation, effect of aNF, 427 Astemizole, 430 as inducer, 336 Atamestane, 289 as substrate, 378, 384, 397, 401, 604, 639 Atrazine, 595 sex-dependence of, 347, 348 ATMP, 278, 279 1,2,3-Benzothiadiazole, 5-6-dichloro, 283, 284 Atomic force microscopy, 95 l,4-Benzoxazine-3-one, 567, 574 Aurones, 570 2,4-dihydroxy-, 566, 566 Autoimmune polyglandular syndrome, 450 2,4-dihydroxy-7-methoxy-, 567 Autooxidation, 153, 156 Benzphetamine, 638 Autumnaline, 205 N-3-Benzylnirvanol, 621, 626 Avermectin, 598-601 N-3-Benzylphenobarbital, 621, 626 Azamulin, 622, 627 Benzyne, 275, 276 2-Azido-3-iodo-7,8-dibromodibenzo-/7-dioxin, 335 Berbamunine, 572 7-(a-azolylbenzyl)-1 H-indoles, 288 Berberine, 571,572 Berberis stolonifera, 205 Bacillus Bergamotin, 394, 430 halodurans, 589 6,7-dihydroxy-, 430 megaterium, 95, 115, 118, 131 Bialaphos, 598 subtilis, 99, 131, 135, 138, 212, 589 Bicyclo[2.1.0]pentane, 9, 12, 68, 187, 188 thermoproteolyticus, 135 Bile acid Baeyer-Villiger reaction, 217, 220, 221, 225 synthesis of, 439, 441, 457 Balhimycin, 206 metabolism, 327 Barbiturates toxicity, 326, 327 and cancer, 396 Bile duct ligation, 364 induction by, 386, 393, 394, 407,424, 431 Bilirubin, 331 metabolism of, 408 Bioavailability, 394, 430 Basic helix-loop-helix domain, 324 Biocatalysts, 133 Benz[a]anthracene, 363, 401 Biotin biosynthesis, 589 l,2-diol,401 /?-Biphenylhydrazine, 274 5,6-diol, 401 Bleomycin, 160 Benzaldehyde, 30, 282 Blood pressure, 543-545 Benzene Blumeria graminis, 591 as inhibitor, 247, 249 BM3R1, 131 oxidation of, 31, 202, 384, 420 Botrotiniafuckeliana, 591 computed mechanism, 75, 76, 79 BRII receptor, plants, 558 oxide, 76, 202 Bradykinin, 542 1,2,4,5-tetramethoxy-, 207 Brassinolide 26-hydroxylation, 555, 558 1-fluoro, 203 Brassinosteroids, 557, 558 l,2-difluoro-,203 biosynthesis, 559, 560 l,3-difluoro-,203 in P450 regulation, 560 poisoning by, 422 Bromotrichloromethane, 281 l,2,3-trifluoro-,203 Bufuralol hydroxylation, 399, 415, 621, 627, 636 1,2,4-trifluoro-, 203 Bupropion hydroxylation, 621, 625 Benzo[6]fluoranthene-9,10-diol, 401 Buspirone, 430 Benzo[c]phenanthrene-3,4-diol, 401 Butadiene, 384, 403 7,8-Benzoflavone, 641 Butanol binding, 646 Benzo[g]chrysene-l 1,12-diol, 401 2-Butene, 185 Benzoic acid oxidation, 226, 603 Buthiobate, 605 Benzo[a]pyrene /er^Butylacetylene, 269 7,8-dihydro-,210 tert-Buty\ methyl ether, 402, 420 662 Index

Butyraldehyde Cannabidiol, 260, 261 ISO-, 221 Capsidiol, 569 2-methyl-, 221 Captopril,418 CAR, see Androstane receptor Caenorhabditis elegans, reductase null, 605 Carbamazepine Cafestol, CYP7A1 inhibition, 441 cooperativity in metabolism, 429 Caffeine hypersensitivity to, 443 cooperativity, 429 P450 inhibition by, 250, 262, 263 drug interaction, 394 as substrate, 21, 386 as P450 substrate, 378, 386, 398-400, 621, 624, 633 Carbene Calcitroic acid, 455 complex, 264, 265, 285 Calcium ring expansion, 14 dependent potassium channel, 538, 541, 542 spin state effects, 11 permeability of membranes, 542 2,3-Z7/5(Carbethoxy)-2,3,-diazabicylo[2.2.0]hex-5-ene, inroleofEETs, 541 275,277 Caldariomyces fumago, 2 3,5-6w(Carbethoxy)-2,6-dimethyl-4-alkyl-1,4- Caloric restriction, 365 dihydropyridine Camalexin, 568 effect on heme biosynthesis, 272 Campestanol, 557, 559 mechanism of oxidation of, 272, 273 Campesterol, 559 metabolism of, 273 Camphene, 66 P450 destruction by, 194, 272, 280, 281, 641 Camphor, 103 Carbofuran, 63, 64 binding, 108, 646 Carbon disulfide, 250 as carbon source, 585 Carbon monoxide hydroxylation of, 6, 134, 152, 191, 595 inabihty to bind, 404 computational studies, 12, 13, 68-72 asligand,51,264, 605 stereochemistry, 3, 64, 65, 186 as metabohc product, 265, 282, 285 product profile, 65 P450 inhibition by, 248, 641 Campylobacter jejuni, 589 differential sensitivity to, 248 CamR repressor, 595 rebinding kinetics, 421, 428 Canadine synthase, 571 cooperativity in, 428, 429 Cancer spectrum of P450 complex, 644 P450 relation to, 395, 422, 430, 443 Carbon tetrachloride, 280, 281, 283, 285, 364, 384, 420 arachidonic acid metabolism, 531 Carboxylic acid bladder, 436 decarboxylation, 226, 227, 562 brain, 460 isotope effects on, 226 breast, 287, 289, 431, 450, 452, 554 radical, 228 carcinoma, 434 Carcinogen activation, human, 384 colon, 396, 400, 460 Carveol, 9 endometrial, 450 Carvone, formation of, 569 esophageal, 404 Castasterone, 559, 560 estrogen-dependent, 401, 402 Castration, 350, 351,543 lung, 395-397, 404, 411, 418, 460 Catalase, 162 lymphoma, 395 Compound 1, bond length, 167 parathyroid, 460 computational studies, 62 prostate, 383, 450, 460, 554 as catalyst, 258, 282 risk, decrease in, 403, 418 catalytic cycle, 150, 151 Candida iron-aryl complex, 274 albicans, 462, 589, 591, 593, 602-609 model, 17 dubliniensis, 591 Catalytic cycle glabrata, 59\,6^^ computed states of, 50 maltosa, 602 gating of cycle, 54, 63 P450 knockout, 602 of P450 enzymes, 3, 48, 49, 150, 153, 155, 184, 606 neoformans, 603 peroxide shunt, 153, 156, 160, 184 tropicalis, 59\, 602 Catalytic species of P450 Candidiasis, 606 see Ferric hydroperoxo Index

Catalytic species of P450 contd. Cholesterol contd. see Ferric peroxo anion homeostasis, 458 see Ferryl species conversion to pregnenolone, 135, 211, 212, 379, 445 Catechol, 1 degradation, in P450 knockouts, 119 Catharantheus rosea, 224, 568 20,22-dihydroxy-, 445 Catharanthine, 569 4[3-hydroxylation, 425 Cathasterone, 558-560 7a-hydroxylation, 379, 439, 440, 621, 631, 637 6-deoxy-, 558-560 24-hydroxylation, 379, 461 Cationic intermediate, 8, 11, 28, 186, 192, 193, 226 27-hydroxylation, 456, 457, 458 Cation radical, porphyrin, 155 in P450 regulation, 439 CBP, 324, 333, 445 side-chain cleavage, see CYPl 1 Al C/EBPa, 361, 405, 408, 413, 425, 433, 451 Cholic acid, 443, 457 Celecoxib, 409 Chorionic gonadotropin, 363 Cembra-2,7,11 -triene-4,6-diol, 554 Chromatin, 324 Cerebrotendinous xanthomatosis, 383, 456 Chrysene Cerivastatin, 407 5,6-dimethyl-l,2-diol,401 COS 16949A,250,287 -l,2-diol,401 CGS 183208,250 5-methyl,401 Chalcone, 570, 571 5-methyl-l,2-diol,401 Chameleon species, see Ferryl species Cicer arietinum (chickpea), 555 Chaperones, 336 Cimetidine, 249, 641 Chenodeoxycholic acid, 440, 443, 457 Cineol, 595 Chlamydomonas reinhardtii, 592 Cinnamate 4-hydroxylation, 555, 557 Chloramphenicol, 250, 254, 255, 363 Cinnamaldehyde, 197, 282 Chloroeremomycin, 206 Circadian rythm, 440 1 -(2-Chloroethyl)-3-cyclohexyl-1 -nitrosourea, 363 Cirrhosis, 362, 364, 402, 430, 441 Chloroform, 384, 420 Cisplatin, 362, 363, 365 Chloromethane, 420 CIS proteins, 361 />-Chloro-iV-methylaniline, 639 Citral, 282 we^fl-Chloroperbenzoic acid Citrulline, 16 as donor to P450, 161 Clofibrate, 331, 332, 354, 402 as donor to P450 model, 20, 21, 23, 32 Clopidogrel,253, 621 oxidation of acetylenes, 198 Clorgyline, 265 oxidation of olefins, 198 Clostridium, 121 P450 inactivation, 283 Clotrimazole, 330, 543, 593 Chloroperoxidase Clozapine, 399 axial ligand, 89 Coactivators, 324, 330, 333 catalysis by, 170 Cobalt, as inducer, 402 Compound I, 3, 60 ^^Cobalt source, 157 inactivation, 269 Cochliobolous lunatus, 586 properties of, 1, 156 Codeine, 365, 573 structure, 2, 89 Colchicine biosynthesis, 205 6-(4-Chlorophenyl)imidazo[2.1-b][l,3]thiazole- Colitis, 24 5-carbaldehyde 0-(3,4-dichlorobenzyl oxime, 330 Complestatin, 206, 599 Chlorpromazine, 365 Compound I, 19, 150-153, 156, 160, 167 Chlortoluron, 566 computed, 50 Chlorzoxazone, 378, 386, 419, 420, 621, 627, 636 orbital occupation, 50 5P-Cholestane-3a, 7a, 12a-triol, 425, 457 see also Ferryl complex 5P-Cholestane-3a, 7a, 12a, 25-tetrol, 457 Compoundll, 19, 151, 160 5P-Cholestane-3a, 7a, 12a, 27-tetrol, 457 Compound III, 156 Cholestanol, 457 Compound Q, 15 Cholestasis, 441 Computation, 45 3 3-Hydroxy-5-cholestenoic acid, 457 ab initio, 46, 47 7a-Hydroxy-3-oxo-4-cholestenoic acid, 457 atomic size parameters, 46 Cholesterol, 457 basis set, 46 biosynthesis, 134 bond energy terms, 47 664 Index

Computation contd. CRE/Adl element, 447, 451 CASPT2 methods, 46, 47 Cre/loxP sytem, 119 CCSD(T) methods, 46, 47 ^ra«5-/7-Coumaric acid, 557 complete active space self consistent field (CASSF), Coumarin, 386, 410, 621 46, 47, 54 3-hydroxylation, 404 configuration interaction, 47 7-hydroxylation of, 378, 403, 404, 405, 621, 624 conformational predictions, 105, 108 CREB, 445 density functional theory (DFT), 6, 11, 12, 13, 45, Cryogenic 46,51,66, 183,201,203 approaches, 3, 150, 157, 161, 185 dynamic electron correlation, 47 radiolysis, 5, 153, 158, 164-167 electronic structure, 45, 46 Cryptococcosis, 606 electrostatic effect, 47, 53, 59 Cryptococcus neoformans, 602 force constants, 46 Cubane, methyl, 192 geometry optimization, 51,52 Cumene hydroperoxide in inhibitor design, 450 as activated oxygen source, 154 Hartree-Fock, 46, 47 heme-protein cross-linking, 281, 430 INDO, 47, 54 Cunninghammela elegans, 591 molecular dynamics simulations, 55, 64, 164, 168 Curyularia sp., 587 molecular mechanic (MM), 45, 46, 63, 65 Cushing's syndrome, 249, 447 Monte Carlo simulations, 63 Cyanide potential energy surfaces, 47 asligand, 156, 167,248 quantum mechanical (QM), 45, 54, 56, 66, 68 as nucleophile, 258, 259, 260, 280 QM/MM,45,51,61,63,68 as product, 560, 563 SAM1,47,49 Cyanogenic glucosides, 553-555, 557, 560-562, 564, Schrodinger equation, 46 565 semiempirical, 46, 47 Cyclic AMP, 445, 449, 454, 461 of site reactivity, 66, 421, 427 Cyclic AMP response element (CRE), 446, 449, 453, of substrate specificity, 64, 65, 66, 68, 404,421 461 spin state, 11, 51, 53 Cycloartenol biosynthesis, 590 strain energies, 46 Cyclobutadiene, 275 valence bond model, 61 Cyclodextrin, 25 van der Waals parameters, 46, 47 Cycloheptenol, 11 wave mechanical approaches, 46, 47 Cyclohexane, hydroxylation of, 7, 28, 30, 31 zero point energy, 71 Cyclohexanecarboxaldehyde, 6, 221 Confocal laser scanning microscopy, 564 Cyclohexanone monooxygenase, 6 Congenital aromatase deficiency, 452 Cyclohexene, 3, 4, 30, 79, 185, 186, 267 Congenital adrenal hyperplasia, 446 3-hydroxymethyl, 11, 15 Conservons, 599, 601 Cyclohexilline, 280 Contraceptive failure, 430, 431 Cyclooctanol, 31 Cooperativity, in P450 Cyclooctanone, 31 early studies, 394 Cyclooctene, 25, 26, 30 heterotropic, 427-429, 428 Cyclopentenyl glycine, 561, 564 homotropic, 427^29 Cyclophosphamide Coregulators, 333, 335 alteration of P450 regulation, 362, 363, 365 Corepressors, 324 oxidation of, 406 Coronary disease, P450 link, 383 Cyclopropane Corticosteroid, 585-587, 610 l-aryl-2-alkyl-, 192 Corticosterone 1-methyl, 188, 192 deficiency disease, P450 link, 383 l-methyl-2-phenyl-, 188 18-hydroxylation, 379, 447 l-methyl-2,2-diphenyl-, 188 Cortisol trans-1 -methyl-2-(4-trifluoromethyl)phenyl-, 190 biosynthesis of, 135, 444, 446, 586 /ra«5-l-phenyl-2-vinyl-, 200 metabolism of, 426 Cyclopropylamine, 196, 283 Corynebacterium diptheriae, 594, 596 N-methyl-N-benzyl, 283 Cotinine, 403 17p-(Cyclopropylamino)-androst-5-en-3|3-ol, 292 CPF, 440 Cyclopropylbenzene, 202 Index 665

Cyclosporin, 281, 363, 386,425, 426, 430 CYP2A6 contd. CYP1A1,377 content in tissues, 382, 385, 391, 402 See Aryl hydrocarbon receptor and cytochrome b5, 403 active site, 397 marker substrate for, 621, 624 in arachidonic acid metabolism, 538 polymorphism, 402-404 content in tissues, 397 regulation/induction, 386, 621 fusion protein with reductase, 133 role in drug metabolism, 386 gene organization, 396 inhibition, 386,404, 621 inhibition of, 397, 632 substrates, 386, 402 interaction with reductase, 129 tissue location, 378, 402 polymorphism of, 395, 397 CYP2A7 reactions, 378 chimeric proteins, 404 regulation/induction, 395, 396 tissue content, 404 in smoking/lung cancer, 395-398 tissue location, 378 substrates, 397, 540, 632 CYP2A13 tissue location, 378, 396, 397 tissue location, 378, 404 CYP1A2, 377 substrates, 405 active site, 399 variants, 405 aldehyde deformylation, 221 CYP2A21,363 in arachidonic acid metabolism, 538 CYP2B 1,560 carcinogen activation by, 384, 396 dehydrogenations by, 209 and colon cancer, 396 disease associations, 404 content in tissues, 381, 382, 385, 391, 398 substrates, 4, 195, 207, 540, 634 cooperativity, 399 and radical clocks, 190 gine organization, 398 regulation/induction, 354, 364 inhibition, 389, 399, 400, 621 threonine, conserved, 302, 256 marker substrates for, 621, 624, 633 CYP2B2, 540 mechanism, 399 regulatory element in, 328 polymorphism in, 398, 400 T302A mutant, 185 prototype inducer, 621 CYP2B4 regulation/induction, 395, 398, 399 aldehyde deformylation, 221 substrates, 207, 399, 540 interaction with b^, 134 tissue location, 378, 398 interaction with reductase, 95, 130 CYPIBI membrane orientation, 129 active site, 402 substrates, 197, 540 carcinogens activated by, 401 structure of, 93 content in tissues, 400 T302A mutant, 191, 222, 258, 282 disease linked to it, 383, 396, 400 CYP2B6 gene organization, 400 active site, 406 inhibition, 402, 633 content in tissues, 382, 385, 405 null mouse, 395, 401 cooperativity, 406 regulation/induction, 393, 395, 400 inhibition, 406, 621 substrates, 380, 400, 401, 402, 633 polymorphism, 406 tissue location, 378,400 regulation/induction, 621, 405 CYP2A1 role in drug metabolism, 386, 406 hormonal regulation of, 349-353, 362, 364 substrates, 406, 621,625 substrates, 633 tissue location, 378,405 CYP2A2 CYP2B10, 328 hormonal regulation of, 349, 350, 353, 354, 363 CYP2B12, 540 male specificity of, 348 cyp2bl9, 540 substrates, 634 cyp2b37, 540 CYP2A6, 377 cyp2b38, 540 active site, 403, 404 cyp2b39, 540 and cancer, 396 cyp2b40, 540 carcinogen activation by, 384, 396 CYP2C family, liver content, 382 diseases associated with, 402 CYP2C 1,540 Index

CYP2C2, 540 CYP2C19co«^^. CYP2C3,221 polymorphism, 394, 407, 411, 412, 413 CYP2C5 regulation/inducers, 386 crystal structure, 88, 93, 94, 100, 102, 105-108, 183 role in drug metabolism, 386 CYP2C6, 634 substrates, 386, 412, 540, 621, 626 CYP2C7 tissue location, 378, 412 induction, 364 CYP2C23, 540, 541,543 hormonal regulation of, 349, 351, 353, 363 CYP2C24, 540 substrate, 635 CYP2C34, 540 CYP2C8, 540 CYP2D2 active site, 407 inhibition, 636 content in tissue, 407 substrate, 636 inhibition, 386, 408, 621, 625 CYP2D6 polymorphism, 407 activesite, 416, 417 regulation/induction, 386, 407, 621 content of tissues, 381, 382, 385, 391,413 structure, 407 dehydrogenation by, 209 substrates, 386, 407, 621, 625 disease links, 418 tissue location, 378,407 fusion protein with reductase, 133 CYP2C9, 377 inhibition, 386, 389, 394, 417, 621 active site, 409,410 mitochondrial, 380 content in tissues, 385,408 polymorphism, 296, 377, 386, 394, 414, 418 cooperativity, 409 regulation/induction, 386, 413 and cytochrome b5, 134, 409 role in drug metabolism, 380, 383, 386, 413 inhibition, 386, 410, 411,621 substrates, 386, 415, 621, 626 polymorphism, 394, 408, 409, 410 surrogate oxygen donors, differences, 416 regulation/induction, 386, 408, 621 tissue location, 378,413 role in drug metabolism, 380, 383, 386, 392, 410 CYP2E1 structure, 93, 410 acetaldehyde deformylation, 221 substrates, 102, 386, 409, 540, 621, 625 active site, 420 tissue location, 378,408 carcinogen activation, 384, 396 CYP2C11 content of tissues, 381, 382, 385, 391, 419 fusion protein with reductase, 133 cytochrome b5 effects, 420 induction, 364 inhibition, 386, 421, 621, 627, 636 hormonal regulation of, 349-355, 357, 361, 363 null mouse, 395, 420, 422 regioselectivity, 540 polymorphisms, 419, 422 sex specificity, 348 regulation/induction, 364, 386, 419, 621 substrates, 540, 635 role in drug metabolism, 386 CYP2C12 structure model predictions, 66 hormonal regulation, 348, 350, 353-355, 361, 363 substrates, 380, 386, 420, 540, 621, 627, 636 substrate, 635 T303A mutant, 185,269 CYP2C13 tissue location, 278, 418, 419 hormonal regulation of, 348-350, 354, 357 CYP2F1 induction, 364 content of tissues, 422 substrate, 635 tissue location, 378, 422 CYP2C18 CYP2J2 content of tissue, 411 polymorphism, 423 inducers, 621 substrates, 423, 538, 540 inhibitors, 411,412, 621 tissue location, 378 polymorphism, 411 CYP2R1,378,423 substrates, 411, 540, 621, 626 CYP2S1 tissue location, 378, 411 induction, 393, 423 CYP2C19 tissue location, 378 active site, 413 CYP2U1,378,423 content of tissues, 381,412 CYP2W1,378,423 cooperativity, 427 CYP3A1 inhibition, 252, 386, 413, 621 dehydrogenation by, 209 Index 667

CYP3A2 CYP4A4, 534 hormonal regulation of, 349, 353, 363 CYP4A5, 534 substrate, 636 CYP4A6, 534 CYP3A4, 377 CYP4A7, 134,534 active site, 426-428 CYP4A8, 534, 537, 545 C-C cleavage, 228 Cyp4al0,534, 537, 538 carcinogen activation by, 384 CYP4A11,534,538 content in tissues, 381, 382, 384, 391, 424 active site, 434, 435 cooperativity, 427 content of tissues, 434 and cytochrome b5, 115, 134, 426 heme covalent binding, 435 dehydrogenation by, 209 inhibitors, 435, 622, 630 disease links, 430 regulation/induction, 434, 622 fusion protein with reductase, 133 substrates, 434, 622, 630 inhibition, 386,430, 621, 627 tissue location, 378, 434 polymorphism, 394 Cyp4al2, 534, 537, 538, 544 regulation/induction, 386, 394, 424, 621 Cyp4al4, 534, 537, 538, 543, 544 role in drug metaboHsm, 380, 383, 386, 392, 425 CYP4A22, 538 structure, 427 content of tissues, 435 substrates, 380, 386, 425, 426, 621, 627 substrates, 534 tissue location, 378,424 tissue location, 378, 435 CYP3A5 CYP4B1 active site, 432 active site, 436 content of tissues, 431 dehydrogenation by, 209 inhibition, 432 disease links, 383 polymorphism, 431 fusion protein with reductase, 435 regulation/induction, 431 heme covalent binding, 436 substrates, 432, 622, 629 substrates, 435, 436 tissue location, 378, 431 tissue location, 378, 435 CYP3A6,221 CYP4F1,533,535 CYP3A7 CYP4F2, 533 active site, 433 inducers, 622 content of tissues, 432, 433 inhibitor, 622, 631 inhibition, 433 substrates, 436, 535, 538, 622, 631 regulation/induction, 433 tissue location, 378,436 substrates, 433, 622, 630 CYP4F3, 533 tissue location, 378,432 substrates, 436, 535 CYP3A9 tissue location, 436 hormonal regulation, 349, 353 CYP4F3B, 535 substrate, 637 tissue location, 378 CYP3A18 CYP4F4, 533, 535 hormonal regulation, 348, 349, 353 CYP4F5, 533, 535 CYP3A23, 636 CYP4F6, 533, 535 CYP3A43 CYP4F8, 533 content of tissue, 434 substrates, 437 regulation/induction, 434 tissue location, 378, 437 tissue location, 378, 434 CYP4F11,533 CYP4A1,537 tissue location, 379, 437 disease links, 383 CYP4F12, 533 fusion protein with reductase, 133 substrates, 622, 631 inhibition, 271, 272, 637 tissue location, 379,437 substrates, 292, 331, 533, 534, 637 Cyp4fl3,533 CYP4A2, 534, 538 Cyp4fl4, 533 disease link, 543 Cyp4fl5,533 hormonal regulation, 353, 537 Cyp4fl6,533 regulation/induction, 364 Cyp4fl7,533 CYP4A3, 364, 534, 537, 538 CYP4F22, 379, 437, 534 Index

Cyp4f37, 533 CYPllAl i?450scc) contd. Cyp4f39, 533 substrates, 445 CYP4V2, 379, 437 tissue location, 379, 443 CYP4X1,379,437 CYP11B1(P45011P) CYP4Z1,379,437 active site, 447 CYP5A1 (thromboxane synthase) adrenodoxin interaction, 447 active site, 439 disease links, 383 disease links, 383 inhibition, 249, 447 inhibition, 439 polymorphism, 446 polymorphism, 438 redox partners, 135 properties, 533 regulation, 446 reaction, 379, 438 substrates, 446, 447 regulation/induction, 438 tissue location, 379, 446 substrates, 438, 439 CYPllB2(P450aldo) tissue location, 379, 437, 438 active site, 448 CYP7A1,327 disease links, 383 actives site, 441 inhibition, 448 content in tissues, 439 regulation, 447 disease links, 383 substrate, 448 inhibition, 441,637 tissue location, 379, 447 instability of, 440 CYP17A1 phosphorylation, 440 active site, 449, 450 polymorphisms, 440 disease links, 383, 450 regulation/induction, 439, 440, 622 effect of cytochrome b5, 134, 448, 449 substrates, 439, 440, 622, 631, 637 fusion protein with reductase, 133 tissue location, 379, 439 inhibition, 292, 450 CYP7B1 mechanism, 216, 449 disease links, 383 mutants, 217 substrates, 441 pH dependence of products, 217 tissue location, 379, 441 phosphorylation, 449 CYP8A1 (prostacyclin synthase) polymorphism, 449, 450 active site, 442 regulation, 449 disease links, 383, 443 substrates, 215, 449 gene organization, 442 tissue location, 379, 448 inhibition, 442 CYP19A1 (aromatase) membrane topology, 442 active site, 452 polymorphism, 442 disease linked to it, 289, 383, 452 properties, 533 gene organization, 451 reaction catalyzed, 379, 438 inhibition of, 248, 250, 271, 286, 287, 289, 452 substrates, 441,442 isotope effects in, 218 tissue location, 379, 442 polymorphisms, 451, 452 CYP8B1 reaction, 6, 217, 218, 219, 451, 452 regulation, 443 regulation, 451 substrates, 443, 622, 631 substrates, 452 tissue location, 379, 443 tissue location, 379, 451 CYPllAl (P450scc),211 CYP20A1,379,452 active site, 445 CYP21A2 adrenodoxin interaction, 445 active site, 453 CO sensitivity, 248 disease links, 383, 453 deficiency, 446 inhibition, 386, 453 disease links, 383 regulation/induction, 386, 453 inhibition, 271, 445 role in drug metabolism, 386 interaction with reductase, 135, 136 substrates, 386, 453 polymorphism, 445 tissue location, 379, 453 reactions, 286 CYP24A1 regulation, 445 active site, 455 Index

CYP24A1 contd. CYP61,602,604 disease links, 383 22-desaturation, 586, 592, 601-603 inhibition, 455 CYP64, 603 regulation, 454, 455 CYP71, 9, 555-557, 562-569 substrates, 380, 455 CYP72, 555, 569 tissue location, 379, 454 CYP73A5, 555, 557 CYP26A1 CYP74A1,555 substrate, 456 CYP74B2, 555 tissue location, 379, 456 CYP75B 1,555 CYP26B1 CYP79, 555-557, 562-566, 573, 574 substrate, 456 CYP80, 555 tissue location, 379, 456 CYP83, 555, 574 CYP26C1 CYP84A1,555 tissue location, 379,456 CYP85, 555, 558, 560 CYP27A1 CYP86A1,555 active site, 458 CYP86A8, 555 disease links, 383 CYP88A, 225, 226, 555 polymorphisms, 456 CYP90A1, 555, 558,560 regulation, 440, 456 CYP90B1,555,560 substrates, 457 CYP93C, 226, 227, 555, 571 tissue location, 379,456 CYP98A3, 555 CYP27B1 CYP101,5eeP450,^ active site, 460 CYP102, see P450BJ^.3 disease links, 383 CYP105, 595, 596, 598-601 gene organization, 459 CYP108,5eeP450j^^p mutations, 459, 460 CYP107A1 regulation, 459 crystal structure, 183 substrates, 460 hydrogen bonding network, 164 tissue location, 379,459 CYP107, 599, 601 CYP27C1,379,460 CYP116,595 CYP39A1,379,460 CYP119,596 CYP46A1,379,461 complex with imidazoles, 100 CYP51 (sterol 14-demethyIase), 555, 590, 594, 601, 602 crystal structure, 88, 91, 100, 183, 601 active site, 462, 609 reaction with peroxides, 3, 161 in azole resistance, 607-609 thermal stability, 91, 601 mutations leading to, 608, 609 CYP121,592,594,598 complementation by, 558 CYP122, 599 and cytochrome bj, 462 CYP123, 594 fusion protein with ferredoxin, 588, 592, 594 CYP124, 594 inhibition, 120,250,603 CYP125, 592, 594, 596, 601 knockout in bacteria, 592, 604 CYP126, 594 phylogram of sequences, 590, 591, 596, 597 CYP128, 594, 598 reaction, 217, 217, 219-221, 379, 585-587 CYP129, 599 regulation, 461 CYP130,594 structure of, 88, 110, 107, 183,462 CYP131,599 substrates, 461 CYP132,594, 598 tissue location, 379,461 CYP135,594,598 CYP52, 602 CYP136,594 CYP54, 603 CYP137, 594, 598 CYP55Al,5eeP450^^^ CYP138, 594 CYP56, 602 CYP139, 594, 598 dityrosine formation, 603 CYP140. 594, 598 CYP57, 603 CYP141.594,598 dityrosine formation, 601 CYP142, 594 CYP58, 603 CYP143, 594, 598 CYP59, 603 CYP144, 594 670 Index

CYP151,598 Cytochrome c peroxidase contd. CYP152A1 properties, 154 reaction, 170 resting state, 51 structure, 170 Cytochrome oxidase, 152, 165 CYP154, 599,601 Cytochrome P450 reductase, 3 crystal structure, 106, 110, 183, 600 alternative electron acceptors, 120 CYP156,599,601 antibodies to, 222 CYP157, 599, 601 fungal, 602, 605 CYP158,600,601 chemical crosslinking to P450, 129 CYP 160, 599 chromosome location, 119 CYP161,599 Class I, 587 CYP 162, 599 Class II, 115,587,589,596 CYP163, 599 determination of activity, 647' CYP164, 592, 594, 598 diversity of, 118 CYP 170, 590, 592, 594, 596, 599 electron flow, 124, 125, 127, 128, 131, 133 gene deletion of, 599 flavin orientations, 96, 97 CYP171,599,601 fusion proteins with, 115, 116, 133, 587, 601, 603 CYP 175 A 1,596 gene organization, 118, 119, 599 structure, 92, 601 hydride transfer, 122, 124, 125, 126, 127 CYP176Al,5e^P450cin inhibition, 123,127,266 CYP178,601 interaction CYP180A1,598,601 with cytochrome b5, 133, 134, 606 CYP181,601 with cytochrome c, 116, 129, 130 CYP504, 586, 587 withP450,95, 116, 128,129, 130 CYP505, 115,603 ionic strength effects, 130 fusion protein, 603 kinetic scheme, 126, 127 CYP701A3, 555 knockout, 119, 120,605 CYP710,592 membrane binding domain, 117, 118, 119, 129 Cysteine ligand, 2, 7, 50, 158 mobility, interdomain, 128-130 bondlength, 57, 59, 61 mutagenesis, 124, 128 effect on iron, 48, 52, 61, 183, 190, 248 NADPH/NADP+ binding, 122, 123, 126-128 in P420, 265 isotope effect, 124, 125 hydrogen bonding to, 48, 89, 186 in CYP55 (P450nor), 587 "push" effect, 48, 52-54, 58, 63, 155 plant, 118, 122,225 and spin state, 48, 157 photoreduction, 96 Cytochrome b5 properties, 117 alternate P450 reductase in yeast, 605, 606 ratio to P450, 129 apocytochrome b5, 134,409, 413, 426, 449 redox properties, 117, 124, 125, 128, 132, 133 complex with P450, 134, 135 regulation/induction, 119, 362, 365 concentration of, 646 structure of, 95, 97, 117, 121, 122, 123, 127 electron transfer to P450, 115 domains, 117, 118, 122, 124, 125, 129, 131 and hemoglobin, 134 truncated forms, 117 interaction with P450 reductase, 120, 133, 134 Cytokines, 388 and lipid biosynthesis, 133, 134 properties of, 133, 134 Dahl Salt Sensitive rat, 543 redox potential, 134 Daidzein, 554, 571 role in vivo, 119, 134 Dapsone, 407, 409, 426 role in individual P450s, 403, 409, 413, 426, 449 Daunorubicin, 599 and uncoupling, 134, 184 DDEP, see 3,5-Z?w(Carbethoxy)-2,6- Cytochrome b5 reductase, 119, 133, 134, 605, 606 dimethyl-4-ethyl-1,4-dihydropyridine Cytochrome c, 120 DDMS, 293 crosslinking to P450 reductase, 129 DDT, 330, 332 inapoptosis, 116 5-Deazariboflavin, 96, 127 Cytochrome c peroxidase Debrisoquine, 378, 383, 386, 621, 626, 636 active site structure, 162 polymorphism, 386, 387, 414, 418 Compound I, bond length, 167 Decalin, 31 Index 671

Decalol, 31 ^m(2,3-Dibromopropyl)phosphate, 384 Deforaiylation, 6 2,2-Dichloroacetamides Dehydration reaction, by P450, 562 N-monosubstituted, 250, 263 Dehydroepiandrosterone hydroxylation, 379,433 2-(/7-bromophenethyl)-, 255 Dehydrogenation, see Desaturation 2-(p-nitrophenethyl)-, 255 5a-Dehydrotestosterone, 544 A^-(l,2-diphenethyl)-,255 Deinococcus radiodumns, 589 2,6-Dichlorobenzonitrile, 405 Delaviridine, 280, 283, 284 1,1-Dichloroethylene, 200, 420, 636 11-Deoxycorticosterone, 447, 453 1,1-Dichloroethylene epoxide, 200 1 l-Deoxycortisol, 453 1,2-Dichloropropane, 420 11-hydroxylation, 379, 446 N-(3,5-Dichloro-4-pyridyl)-4-methoxy-3-(prop-2- 6-Deoxyerythronolide B, 90, 103, 163 ynyloxy)benzamide, 272 Deprenyl,258,259,415 3-[2,3-Dichloro-4-(2-thenoyl)phenoxy]propan-1 -ol, Desaturation, 210 621,626 acetaminophen, 211 1,4-^/5[2-(3,5-Dichloropyridyloxy)]benzene, 329 cytochrome b5 electron donor, 133 3-[2,3-Dichloro-4-(2-thenoyl)phenoxy]propan-l-ol, 411 dihydropyridine, 211 Diclofenac, 100, 102, 105, 107, 283, 284, 394, isotope effects, 209, 210 409^11,621,626,635 hydrocarbon, 134, 208-211 cooperativity in metabolism of, 428, 429 lovastatin, 425 Dictyostelium discoideum, 591, 610 mechanism, 209 Dieldrin, 189 3-methylindole, 211,422, 436 Diet, effects on P450, 364, 365, 430, 536, 537, 541, 543 sterol, 210, 586, 592, 601-604, 608 Diethyldithiocarbamate, 250, 404, 421, 621, 627 substrates for, 208 Diethylnitrosamine, 277, 384 see Valproic acid 2,2-Diethyl-4-pentenamide, 268 Desferoxamine, 258 l,2-Difluoro-4-iodobenzene, 17 Desulfuration, 251 Dihydralazine, 275 Detergent, non-ionic, metabolism of, 425 24,25-Dihydrolanosterol, 462 Dexamethasone Dihydroquinolines, 2,2-dialkyl, 273 in decrease of CYP2C11, 363 6' ,7'-Dihydroxybergamotin, 250, 261 as inducer, 324, 325, 326, 386, 408,412, 424,434, 1,25-Dihydroxycholecalciferol, 451 438,621 7a,27-Dihydroxy-4-cholesten-3-one, 457 Dextromethorphan, 265, 426, 621, 627 7a,12a-Dihydroxy-4-cholesten-3-one, 457 cooperativity in metabolism of, 429 3p,7a-Dihydroxy-5-cholestenoic acid, 457 Developmental effects, 388, 432 7a,27-Dihydroxycholesterol, 457 DHEA,441,449 la,25-Dihydroxyvitamin D3, 425, 454, 455 16-hydroxy, 452 24,25-Dihydroxyvitamin D3,460 -3-sulfate, 622, 630 Diltiazam, 622, 629 Dhurrin, 557, 561, 562-564, 573 1,1 -Dimethylallene, 283 Diabetes effects on N,N-Dimethylaniline, see Aniline drug metabolism, 365,422 7,12-Dimethylbenz[a]anthracene, 363, 395, 401 fatty acid oxidation, 531 3,4-diol,401 P450 expression, 362, 363, 364, 419, 537 N,N-Dimethylbenzamide, 195 manganese porphyrin effect on, 24 4,4-Dimethylbiphenyl, 64 Diallylsulfide, 254, 268 Dimethylnitrosamine, 384, 420 Diallylsulfone, 254, 268, 636 cis-3,4-Dimethyl-2-(3-pyridyl)thiazoHdin-4-one, 403 Dibenzo[<3,/]pyrene, 401 Dimethyl sulfide, 76 ll,12-diol,401 1,7-Dimethylxanthine, 403 2,3-Diazabicyclo[2.2.0]hex-5-ene, 277 1,8-Dinitropyrene, 401 Diazenes, 275 Diol, cleavage of, 211, 212 Diazepam, 426 Dioxin response elements, 337, 338 12,12-Dibromododec-ll-enoic acid, 293 Dioxygenase reductase, 588 2,3-Diazabicyclo[2.2.0]hex-5-ene, 275 Dioxiranes, 222, 223 Diazinon, 413 Disease links to mutations, 383 Dibenz[a,h]anthracene, 363 Disulfiram,386,404,421 1,2-Dibromoethylene, 420 Dityrosine, 601-603 672 Index l,2-Dithiole-3-thione, 254 Epipodophyllotoxin, 431 Diuron, 566 Epitope mapping, 93 DMZ, 101, 102, 106, 107 Epothilone, 99, 103,595 DNA binding domain, 323 Epoxidation DNA microarrays, 334 charge transfer, 269 Docetaxel, 431 electronic effects, 73, 185, 203 11-Dodecenoic acid, 211 see Heme adducts 10-Dodecynoic acid, 294 mechanism, 6, 73, 198, 269 11-Dodecynoic acid, 250, 293 see Metalloporphyrin Doxorubicin, 120 olefins, 185 DR-1,440 orbital diagram of ferryl, 67, 73, 74 Drosophila, 553 see Acetylenes, oxidation of Drug interactions, 389, 394, 430 see Aromatic rings, oxidation of DTT, 104 stereochemistry, 19, 198 Dwarfism, in plants, 556, 558, 560 versus hydroxylation, 79 4p,5p-Epoxyandrostenedione, 290 Ebastine, 437 Epoxide hydrolase, 392, 539 Eburicol, 604 24(5)-Epoxycholesterol, 440 Econazole, 593 EPR, 17, 21, 33, 54, 156-160, 165, 167, 185, 191, EDHF, 540, 542 194,207 EETs Ergosterol biosynthesis, 120, 210, 586, 592, formation by P450, 292, 423, 533, 539, 541, 545 602-605, 610 in glycerophospholipids, 541, 542 Erythromycin metabolism of, 553 biosynthesis, 163, 598-600 physiological properties, 293, 541 breath test, 426 role in membrane biology, 293 as inhibitor, 265, 394, 430 5,6-EET, 533, 535, 539, 542, 543 as substrate, 386, 425, 426, 428, 621, 628, 637 8,9-EET, 533, 535, 539 Equilenin, 205 11,12-EET, 535, 538, 539, 540, 542 ERK1,455 14,15-EET,533,545,539 ERK2, 455 EGF signaling, 541 ERK5, 455 Eicosanoids, 531-534, 543 Esterase, 392 metabolism of, 380, 533, 535 Estradiol Electric field, protein, 51 biosynthesis, 450, 452 Electron correlation, 47 metaboHsm, 204, 378, 380, 384, 399, 400, 401, 633 Electron density, 191 enhancement by aNF, 427 unpaired, 186, 204 in P450 regulation, 363, 364 Electron transfer, 115, 124 Estriol, 452 conformational gating, 128 Estrogen partners, classes of, 115 biosynthesis, 218 pathway, 96, 127 -dependent tumors, 401, 402 toP450, 183, 124-128, 131-133 in P450 regulation, 351, 440 from radical to iron, 192 Estrone, 204, 399, 401, 450, 452 see SET mechanism Ethane, 69, 71,267 Electrostatic terms, 51 Ethanol Ellipticine, 398, 641 asinducer, 364, 386, 621 Embryogenesis, 119 as substrate, 418, 419, 421 Endocrine regulation, 347, 348 tolerance of microbes, 586 Endoplastic reticulum proliferation, 328 4-Ethinylbiphenyl, 271 Endotoxin, 440 7-Ethoxycoumarin, 258, 260, 260, 406,422, 621, 639 ENDOR, 17, 161, 165, 185, 191, 192 isotope effect on oxidation, 194 Enhancer elements, 324, 328, 336, 405 7-Ethoxyresorufin, 397, 400, 621, 624 Enthalpies of formation, 47 7-Ethoxy-4-(trifluoromethyl)coumarin, 258, 621, 639 Epidermin, 565 Ethyl carbamate Epidermophyton spp., 603 activation of, 384, 420 Epiheterodendrin, 564, 565 desaturation of, 211 Index 673

Ethyl methanesulphonate, 556 Ferric hydroperoxo contd. Ethylbenzene oxidation, 9, 163 bond length, 57 stereochemistry, 9, 25 in amine oxidation, 197 Ethylene in olefin epoxidation, 201 from diethylnitrosamine, 277 dissociation, in peroxidases, 154, 160 computational studies of oxidation, 6, 73, 74, 77, 201 EPR parameters, 159 heme N-alkylation, 74, 199, 255, 267, 268 as P450 intermediate, 3, 5, 48, 56, 151, 153, 156, Ethylene glycol, in radiolysis, 158 157, 183 2-Ethylhexanoic acid, 209 pH dependence of role, 217 2-(Ethylhexyl) phthalate, 332 pKa, 57, 59 Ethylmorphine, 347, 348, 639, 646 protonation, 54, 56, 58, 63, 155, 158, 164 19-(Ethyldithio)androst-4-ene-3,17-dione, 289 spectrum of, 160 7-Ethynylcoumarin, 250, 258, 259 spin state, 155 17a-Ethynylestradiol, 250, 256, 258, 259, 394, 406, stability of, 157 423,430,431 structure, 57 1-Ethynylnaphthalene, 250 Ferric hydrogen peroxide complex, 51 2-Ethynylnaphthalene, 250, 257, 258, 263, 271 Ferricyanide, 274 2-Ethynylphenanthrene, 271 Ferrocene, 102, 108 3-Ethynylphenanthrene, 271 Ferrous dioxygen complex 9-Ethynylphenanthrene, 271, 625, 634 computational studies, 54-57, 168 np-Ethynylprogesterone, 250, 256, 257 pKa, 56 18-Ethynylprogesterone, 447 as P450 intermediate, 3, 48, 150, 151, 153, 183 1-Ethynylpyrene, 250, 256, 257, 270, 271, 285 protonation of, 56, 57, 63, 155, 156, 161 2-Ethynylpyrene, 402 radiolysis of, 166 Evolutionary relationships, 541, 555, 567, 596 resonance Raman of, 156 EXAFS, 17 spectrum of, 160 Exemestane, 288, 289, 452 stabilization of, 55, 167 Expressed sequence tag (EST), 554, 557, 567, 575 structure of, 167 Ezlopitant, 209, 427 Ferryl species, 6, 48, 59, 183 and active site polarity, 79 FAD, 115, 116, 118 calculations on, 51, 66, 77, 78 affinity for, 122 chameleon species, 60-63, 79 domain, 121, 127 electronic state, 59-62, 66, 67, 72, 74, 77 reduction of, 124, 126, 133 formation of, 3, 58, 155, 156, 161 Fadrozole, 287 electrophilicity of, 77 Farnesoid X receptor (FXR), 440, 443 ligand dependence of properties, 59 Fasting, 331, 334, 537 role in substrate oxidation, 8, 11, 150, 151, 153, 186, Fatty acid, 131 192 o) and (0-1 hydroxylation, 213, 292, 378, 420, 434, structure, 167 435, 532, 535-537, 539, 545, 555, 621, 631 see also Compound I w-2, (0-3 hydroxylation, 621, 631, 595, 596 Ferulic acid hydroxylation, 555 metabolism, 330, 331, 380, 603 a J-Fetoprotein transcription factor (FTF), 443 P-oxidation, 539 Fexofenadine, 394 Felbamate, 429 Filipin biosynthesis, 601 Feminization, 446 Finasteride, 425 Fer, 135 FK506,281,598 Ferredoxin, 115, 135 Flash photolysis, 127, 136 fusion protein with, 588, 592, 594 Flavin-containing monooxygenase, 6, 253 Ferredoxin reductase, 115, 118, 135 Flavin hydroperoxide, 6 Ferric peroxo anion, 5, 6, 150, 155, 183, 185, 215, 217, Flavanone, desaturation of, 211 219,220,222 Flavodoxin, 118, 120, 121, 132, 138,213 computational studies, 54, 55 as redox partner to P450cin, 588 reaction with nitrile, 425 as fusion domain on P450, 588 Ferric hydroperoxo Flavodoxin reductase, 588 as oxygen donor, 5, 6, 19, 66, 77, 152, 185, 186, Flavonoid 190-192 biosynthesis, 570 674 Index

Flavonoid contd. Glucosinolates, 553-555, 557, 564, 565, 574 3'-hydroxylase, 555 Glutathione, 24, 539 6-hydroxylase, 569 Glutathione reductase, 98 Flavones, 394 Glutathione transferase, 539 Fluconazole, 250, 290-293, 386, 432, 604, 605 Glycerol, effects of, 128, 158, 159 resistance to, 606, 608, 609 Glycine max (soybean), 566, 569, 571 structure of, 607 /'-Glycoprotein, 394, 424, 426 Fluometuron, 566 Glycyrrhiza echinata (licorice), 571 Fluorescence Gonadal hormones, 350, 366 emission, 126 Grapefruit juice, 261, 262, 394,430 quenching, 428 Green fluorescent protein, 563 Fluorescent reporter group, 103 "Green pigment", 267, 277, 278 Fluoranthene-2,3-diol, 401 GRIP-1,330 15a-Fluorolanost-7-en-3p-ol, 291 Griseofulvin, 278, 279, 402 20-Fluoro-17(20)-pregnenolone, 292 Grotthuss mechanism, 56, 162 5-Fluorouracil, 363 Growth hormone Flurbiprofen, 409 age-dependence, 350 Fluroxene, 268 in regulation of P450, 350, 351, 354, 359, Fluvoxamine, 386, 399, 642 363, 459 FMN, 115, 116, 118, 132 receptor, 355-357, 362 affinity for, 121 secretory pattern, 351-353, 355-360 binding domain, 120, 121, 129 alteration by xenobiotics, 363, 364 reduction of, 124 GSTYa, 338 Formic acid, as product, 282, 283 Gynecomastia, P450 link, 383 Formononetin, 571 Forskolin, 459 Halobacterium NRCl, 589 FprA, 125, 127, 135 Halocarbons, 263, 283, 285 Furafylline, 279, 285, 386, 399, 400, 621, 624, 633 Halothane, 285, 403, 420, 422 Furan oxidation, 261, 262, 280 Hammett relationship, 28, 185, 195, 197 Furanocoumarins, 250, 261, 430, 553 HAT mechanism, 196, 197, 204, 211, 228 Fusarium oxysporum, 115, 169, 603 HDL, 541 Fusion proteins, 115, 116, 133, 435, 587, 588, 592, 594, Heart disease, 287 601,603 Heat shock protein. See Hsp90 see P450BM-3 Helianthus tuberus (artichoke), 555, 557 Helicoverpa zea (corn), 553 Galangin,621,624, 633 Helminthosporium turcicum, 568 Gender effects, see Sex-linked differences Hematinic acid, 282 Gene duplication, 414 Heme Gene knockout mice, see Null mice adducts of, 260, 267, 272, 273, 281, 283 Gene organization, 555, 567 meso-a\ky\-, 222 Gene therapy, 454 N-alkyl/arylation of Genistein, 454, 554, 571 mechanism, 74, 75, 199, 201, 256, 257, 276 Genomes myoglobin, 274 bacterial, P450 enzymes in, 589, 599 regiochemistry, 268, 270, 274, 278 human, P450 enzymes in, 347, 378 reversibility, 269 Geosmin, 598, 601 stereochemistry, 268 Geraniol, 569 bleaching, 282 Gestodene, 250, 253, 270, 285, 386, 430, 432, 621, 628 carbene complexes, 264, 265, 285 GH, See Growth hormone covalent binding to protein, 435, 436 Giardia lamblia, 590 of fragments, 280, 281, 430 Gibberellafujikuroi, 226, 229, 603 iron-alkyl/aryl complexes, 273, 274, 275, 285 Gibberellin biosynthesis, 225, 228, 229, 603 irradiation to disrupt complexes, 264 Glaucoma, P450 link, 383, 396, 400, 401 nitroso complexes of, 266 Glucocorticoid, 324 quantitation of, 645 receptor, 326, 446 reduction potential, 89 (3-Glucosidase, 560 Heme degradation, 155, 251 Index 675

Heme oxygenase, 120, 150, 151, 153 Horseradish peroxidase hydroperoxo complex, 159 axial ligand, 51 Hemoglobin, 156, 195,281 catalytic residues, 154 hydroperoxo complex, 158, 159 Compound I, 195 iron-aryl complex, 274 iron-oxygen bond length, 167 Hepatic toxicity, 253, 275 rate constants for formation, 154 Heptamylose sugars, 25 Compound III, 156 Hepatocyte nuclear factors, See HNF computational studies, 62 Hepatitis A, P450 decrease due to, 404 ferric hydroperoxo complex, 158, 159 Hepoxilins, 531 substrate peroxidation, 207 Herbicides, 553, 556, 566, 595, 598, 599 substrate peroxygenation, 196, 198 HET0016,293,622,630 Host-guest complex, 25 HETEs 15-HEPTE, P450 role, 532, 533 formation by lipoxygenases, 531 Hsp90, 336, 337, 397 formation by P450, 292, 536 Humoral hypercalcemia, 459 metabolism by P450, 294, 553, 535 Hydrazines, 274 physiological roles, 293, 294 acyl-, 263 5-HETE, 535 l,l-dialkyl-,263,275 9-HETE, 535 heme destruction by, 273, 275, 281 12-HETE, 535, 536 hemoprotein complexes of, 266, 267, 274 15-HETE, 535 radical formation from, 273 16-HETE, 535 Hydrocortisone, production of, 586, 587 17-HETE, 535 Hydrogen bonds, low energy, 57 18-HETE, 535 Hydrogen peroxide, 281 19-HETE, 535, 538 Hydroperoxide, see Oxygen donors 20-HETE, 535, 538, 543-545 Hydroperoxide lyase, 555 vasoconstrictor, 538, 542, 543 20-Hydroperoxycholesterol, 286 Hexane, 1-hydroperoxy, 5 10-Hydroperoxy-4-estren-3,17-dione, 290 3,4,5,3',4',5'-Hexachlorobiphenyl, 363 Hydrostatic pressure, 165, 429 15-Hexadecynoic acid, 294 N-Hydroxy-2-acetylaminofluorene, 3 84 Hexahydro-l,3,5-trinitro-l,3,5-triazine, 588 4-Hydroxyandrost-4-ene-3,l7-dione, 289, 290 Hexamethylphosphoramide, 403,405 ;7-Hydroxybenzaldehyde, 561 3-Hexene, 267 N-Hydroxy-N' -(4-butyl-2-methylphenyl)formamidine, Hexobarbital, 347, 348, 408, 412, 646 293 3-Hexyne, 283 5-exo-Hydroxycamphor, 167, 595 HIFla and related, 338 dehydrogenase, 595 Histone deacetylase, 324 7a-Hydroxycholesterol, 457 HIV protease inhibitors, 430 20-Hydroxycholesterol, 440 HNF, 387, 398, 443 24-Hydroxycholesterol, 440 HNFla,361,419,433 7-hydroxylation, 379, 440, 460 HNF3P,361,433 25-Hydroxycholesterol, 440, 441 HNF4a, 326, 330, 361, 402, 408, 413, 425, 433, 440, 27-Hydroxycholesterol, 440, 459 443 6p-Hydroxycortisol, 426, 621 HNF6, 361 8-Hydroxyeicosatetraenoic acid, 436 Homology models, see Sequence, structure models 12-Hydroxyeicosatetraenoic acid, 436 Hordeum vulgare (barley), 555, 561, 564, 566 12-Hydroxyheptatrienoic acid, 439 Hormone 12-Hydroxy-8,10-heptadecadienoic acid, 439 deficiencies, sex hormones, 383 12-Hydroxy-5,8,10-heptadecatrienoic acid, 547 gonadal, 350, 366 12-Hydroxy-5,8,10,14-heptadecatetraenoic acid, 439 see Growth Hormone Hydroxylamines, 266 luteninizing, 363 11 P-Hydroxylase, see CYPl IB parathyroid, 454, 459, 538 17a-Hydroxylase/C 17,20 lyase, see CYP17A phytohormones, 554, 556, 558, 569, 574 Hydroxylation replacement therapy, 450 alkane, 7, 186 status, 347 allylic, 4, 9, 68, 70, 72, 73, 185, 535, 536 see Thyroid hormone barrier height, 12, 47, 70, 71, 72, 161 676 Index

Hydroxylation contd. Indole-3-glycerol phosphate, 567, 568, 574 benzylic, isotope effects, 196 Indolin-2-one, 567 bond strength, 30, 66, 196 3-hydroxy-, 567 hydrogen abstraction, 189, 193, 212 Indomethacin, 227, 285 see Isotope effects, hydroxylation Induction ofP450, 324, 621 mechanism, 186, 191 barbiturates, 386, 393, 394, 407, 424, 431 prediction of site reactivity, 66, 421, 427 charred food, 387, 399, 621 radical intermediate in, 12, 13, 66, 193, 212 clofibrate,331,332,354,402 rearrangements, 9, 68, 186 cruciferous vegetables, 399, 621 rebound mechanism, 192, 193 DDT, 387 stereochemistry, 4, 5, 9, 186, 193 dexamethasone, 324, 386, 408, 424 transition state, 4, 9, 11, 67, 69, 71 diphenylhydantoin, 387, 396 tunneling effects, 14 ethanol, 364, 365, 386, 387 versus epoxidation, 79 exercise, 399 Hydroxyl radical isoniazid,386,418,419, 621 formation, 155 mechanism of, generalized, 388 quenching, 159 PCN, 324 /7-Hydroxymandelonitrile, 561, 562, 563 phenobarbital, 402, 408, 412, 621 a-Hydroxynitrilase, 560 pharmacokinetic effects, 393, 394 ^ra«5-4-Hydroxy-2-nonenal, 283 polychlorinated biphenyls, 387, 397 4-Hydroxyphenylacetaldoxime, 555, 557, 561, 562 poly cyclic aromatic hydrocarbons, 419 /7-Hydroxyphenylacetonitrile, 561 via protein stabilization, 266, 399, 419, 425 7a-Hydroxyprogesterone 12-hydroxylation, 379 pyrazole, 402 17-Hydroxyprogesterone 21-hydroxylation, 379,453 see Regulation 12-Hydroxystearic acid, 436 rifampicin, 325, 386, 387, 394, 402, 407, 408, 412, la-Hydroxyvitamin D3, 458 424,431,433,434 2 5-Hydroxyvitamin D3 via RNA increased translation, 419 la-hydroxylation, 460 via RNA stabilization, 419 24-hydroxylation, 379 smoking,386, 397, 399, 621 hydroxylation pathways, 455 St. John's wort, 430, 431 Hyperaldosteronism, 447 troleandomycin, 621, 637 Hypercholesterolemia, P450 link, 383 TCDD, 335, 397, 538 Hypercortisolism, 249 Inflammation, 24 Hyperglycemia, 363 P450 link to, 383, 402 Hyperketonemia, 363 Inhibition, 389 Hyperlipidemia, 363 acetylenes, 199,399 Hyperoxysterolemia, P450 link, 383 AIA, 255, 267, 268, 641 Hypersensitivity, idiosyncratic, 262, 410, 422, 443 aldehydes, 222 Hypertension, 253, 383, 447, 531, 532, 537, 542 1-aminobenzotriazole, 275, 276, 294, 641 Hypervitaminosis D, 455 by antibodies, 390-392 Hypoglycemia, 334 diagnostic, 621 Hypophysectomy, 351, 353, 355, 357, 362 mechanism-based, 247, 394, 430, 447, 450, 452 Hypothalamic-pituitary axis, 351, 363 allosteric stimulation of, 428 Hypothyroidism, 362 heme modification by, 250, 256, 257, 260, 263, Hypoxia inducible factors, 120, 338 267, 284 protein modification by, 250, 252, 253, 254, 256, Ibuprofen, 410 259, 262, 263, 267, 271, 404, 406, 410 Imidazole carbon monoxide, 248, 641 binding of, 435 computational studies of binding, 64 in P450 inhibition, 249, 593, 605 cyclopropylamines, 196 structure of P450 complex, 100 dihydropyridines, 272, 641 10-Imidazolyldecanoic acid, 622, 630 glutathione as test of type, 251, 252, 258, 259, 261, Imipramine, 365 262,275, 280 Indigo, 403, 420 hydrazines, 267 Indole, 403, 420, 567, 568 iron coordination, 247, 274, 543 Indole-3-acetaldoxime, 555 isoform selectivity, 251, 252, 255, 261, 271, 275 Index 677

Inhibition contd. Isotope effects contd. metabolic intermediate (MI) complex, 262, 263, 264, intrinsic, 188 265, 425, 645 inverse, 198, 202, 203 olefins, 199 masking of, 64 quasi-irreversible, 247, 250, 265 in oxidation of acetylenes, 270 partition ratio, 199, 252, 253, 257, 260, 267, 270, 279 in oxygen activation, 417 substrate competition, 247 solvent, 56, 128, 164, 165 surfactants, 285 Isovaleric acid decarboxylation, 226 sydnones, 277, 278 Issatchenkia orientalis, 591 types, 247 Itraconazole, 593, 605 Insect attractants, 554 resistance to, 608, 609 Insects, 590, 592 structure of, 607 Insecticide resistance, 553 Insulin, 364, 365, 440, 537 Jak2, tyrosine kinase, 357-359 Interferon-7 response element, 442 Jasmonate, 553, 569 Interleukins, 419, 425, 440,451 lodosobenzene, see Oxygen donors Kaempferol, 408 Ion channel regulation, 542 ent-Kaurene oxidase, 555 Ifosphamide, 362, 363, 365 e«^Kaurenoic acid, 225, 555 Indinavir, 425 Kavapyrones, 430 4-Ipomeanol, 422, 436 Ketamine, 406 Irbesartan, 411 Ketene, 257, 258 Iron-sulfiir protein, 115, 116 Ketoconazole, 120, 249, 253, 290, 291, 386, 394, 430, Isoandrocymbine, 205 432, 433, 593, 604, 621, 642, 450 Isocyanate, a-keto-, 253 resistance to, 605, 606, 609 Isocyanide complexes, 169, 644 structure of, 607, 628, 642 Isoflavone synthase, 227, 228 suppression of P450 expression, 424 Isoflavonoids, 553-555, 569, 570 Ketoprofen, 227 Isoflurane, 420 L-Isoleucine, glucoside precursor, 561, 564, 565 L-754,394, 250, 262 Isoniazid, 266, 386, 404, 418, 419 Langmuir-Blodget, 95 Isonitriles, as product, 285 Lanosterol, 1, 219, 461, 592, 605 Isoporphyrin, 222 Lanosterol 14-demethylase, see CYP51 2-isopropenyl-2-methyladamantane, 406, 621, 625 Laser flash photolysis, 9, 96 3-Isopropenyl-3-methyldiadamantane, 406, 621, 625 Laurie acid oxidation 2-lsopropyl-4-pentenamide, 255, 267, 641 desaturation, 211 i^O-studies, 268 reconstitution of activity, 117 Isosafrole, 264, 282, 399 as substrate, 132, 283, 378, 380, 420, 434-436, 533, Isothermal titration calorimetry, 98, 135 537, 538, 622, 630, 637 Isothiocyanate, 250 LDL, 541 benzyl-, 254 Leischmeinia, 610 ^butyl-, 254 Lens culinaris (lentil), 571 phenyl-, 254 Letrozole, 287, 288 Isotope effects Leucoanthocyanidins, 570 ir-bond oxidation, 207, 270 Leukotriene B4 hydroxylation, 378, 436, 437, 534, 535, on carcinogenicity of nitrosoamines, 421 621,631 in heteroatom dealkylation, 194, 265, 399, 417 Leukotrienes in elimination reaction, 223, 272, 283 in physiology, 332 effect of reorientation in site, 64 metaboUsm, 294, 352, 378 on enzyme inactivation, 279, 283 L-Leucine, glucoside precursor, 561, 564 on hydroxylation, 186, 193,427 Lidocaine, 365, 426, 636 acetaldehyde, 421 Ligand, axial alkyl,4,8,30,68, 164, 189 ammonia, 54 allylic, 4, 9 calculations on, 51, 52, 59, 61 benzylic, 64 catalase, 51 ethanol, 421 see Cysteine ligand 678 Index

Ligand, axial contd. Manganese porphyrin contd. imidazole, 51 stereoselective oxidation by, 25, 26 protein environment effects, 52 Manihot esculenta (cassava), 557, 561 and spin state, 48, 157 Marmesin, 186,223 thiolate ligand, 48, 49 MDL 19347, 292 effect of structure on, 60, 61 Meander region, 95 effect on iron, 48, 52, 61, 183, 190, 248 Mechanism-based inhibitors, see Inhibition thiolate ligand equivalents Medicago methoxide, 62 5fl?/vfl (alfalfa), 555,571 methyl mercaptide, 49-51, 59-61, 69, 70 truncatula, 575 thiolate (SH-), 50, 60, 70 Medicarpin, 571 thiophenoxide, 51 Meloxicam, 428 water as 6th ligand, 48, 65, 192 Membrane Ligand binding domain, 323 binding of P450 to, 92, 93, 442 Limonene, 9, 569 heme relative to, 93, 95 Linamarin, 564 insertion sequence, 92, 93 Lindane, 210 model phospholipid depth, 95, 129 Linear free energy relationships permeability to calcium, 542 inactivation by cyclopropylamines, 273 phospholipid monolayers, 95, 129 substrate oxidation, 427 targeting to membrane, 92 Linker domain, P450 reductase, 120, 121 targeting to in mitochondria, 92 Linoleic acid topology, 129 oxidation of, 187,409,423 Mentha sp., 569 as PPAR ligand, 332 Menthofuran, 261, 404, 621, 624 Linum usitatissium (flaxseed), 555 Menthol, formation of, 569 Linuron, 566 Mephenytoin, 378, 386, 406-408, 412, 621, 625, 626 Lipase, 117 19-Mercapto-androst-4-ene-3,17-dione, 289 Lipid peroxidation, 403, 422 10-P-Mercaptoestr-4-ene-3,17-dione, 290 Lipoxins,, 436, 531, 535 Metabolic intermediate complexes Lipoxygenases, 531, 536 properties, 262, 263, 264, 265, 425 Liquiritigenin, 571 spectra, 645 Lithocolic acid, 327, 440 Metabolon, 563, 574 LKMl, see Antibodies Metallocorroles, 19 Loganin, 224, 571 Metalloenzymes, 150 Losartan, 409, 411 Metalloporphyrin, 62 Lotaustralin, 564 activation of dioxygen, 6-10, 155, 157, 159 Lotus japonicus, 571 amphiphilic, 24 Lovastatin, 425 chiral oxidations by, 25, 26 desaturation of, 210 hydroxylation, 17 LRH-1,451 see Manganese porphyrin LTB4, see Leukotriene B4 olefin epoxidation, 17, 18-21, 26, 535 Lupinus sp., 671 radical cations, 17, 18, 207 Luteinizing hormone, 363 Methane, 11, 68, 69, 71, 72, 590 LXRa,440,461 Methane monooxygenase, 15, 164 LXRP,440,461 Methanosarcinia barkeri, 589 Lycopersicon esculentum (tomato), 555 Methemoglobin reduction, 134 Lysine acylation, 254 Methemoglobinemia, 134, 394, 400 Methimazole, 362 Macarpine, 572 Methionine N-hydroxylation, 555 Magnetic circular dichroism, 156 Methionine synthase, 134 Major histocompatibility locus, 453 reductase, 118, 120, 124, 125, 132 Malondialdehyde, 439 Methoxsalen, 250, 261, 386 Manganese porphyrin, 8, 19-22, 51, 62 2'Methoxyacetophenone, 405 as haloperoxidase, 22, 23 3-Methoxy-4-aminoazobenzene, 401, 436 oxygen exchange in reaction, 19,20, 22 Methoxychlor, 330 peroxynitrite reaction, 23, 24 18-Methoxycoronaridine, 412 Index 679

S-Methoxy-A'^TV-dimethyltryptamine, 416 Mitogen, 541 Methoxylamine, 261 Mitomycin c, 120 3-Methoxyphenethylamine, 416 MKP-1,449 4-Methoxyphenethylamine, 416 Molecular dynamics, see Computation 8-Methoxypsoralen, 250, 404, 621, 642 Monosodium glutamate, 353, 355 Methoxyresorufin, 633 Morpholine, 598 8-Methoxypsoralen, 263 Morphine biosynthesis, 463, 554, 572, 573 5-Methoxytryptamine, 416 Mortierella isabellina, 198 9-Methylanthracene, 207, 208 Mossbauer, 17, 156, 158,267 14a-Methyl-15-aza-D-homosterols, 291 computed parameters, 45, 54 N-Methylcoclaurine 3'-hydroxylation, 557, 571, 572 MSPPOH, 293, 294 3-Methylcholanthrene, 335, 336, 363, 398 Musca domestica, 222 Methylcyclohexane, 31 Mycobacterium 6-Methyleneandrosta-1,4-diene-3,17-dione, 289 avium, 591 4,4'-Methylene-bis(2-chloroaniline), 384, 428 CYPome of, 594, 598 Methylenedioxy carbene complex, 264, 645 bovis, 589, 592, 593 Methylene chloride, 420 CYPome of, 594, 598 Methylenedioxy compounds, 263, 571 chelonei, 592, 593 Methylenedioxy bridge, formation of, 571-573 fortuitum, 592, 593 14-Methylergosta-8,24(28)-dien-3,6-diol, 604, 608 leprae, 589, 592, 594, 596 14-Methylfecosterol, 604, 608 CYPome of, 594, 598 2-Methyl-l-heptene, 267 marinum, 591 3-Methylindole smegmatis, 589, 591-593, 596 desaturation of, 211, 422, 436 CYPome of, 594, 596, 598 P450 inactivation by, 280, 378 phylogenetic tree, 596, 597 4-Methyl-N-methyl-N-(2-phenyl-2H- tuberculosis, 125, 127, 135, 589, 590-593, 596, 609 pyrazol-3-yl)benzenesulfonamide (DMZ), 101 CYPome of, 594, 596 4-(Methylnitrosamino)-1 -(3-pyridyl)-1 -butanol, 3 84 phylogenetic tree, 596, 597 4-(Methylnitrosamino)-1 -(3-pyridyl)-1 -butanone, 378, Mycosphearella graminicola, 591 384, 403 Mycotoxin biosynthesis, 603 Methylococcus capsulatus, 588, 590, 591, 594 Myeloperoxidase, 1 fusion protein with ferredoxin, 592, 594 Myoglobin 4-Methylpentanal, 211, 212, 445 engineering of, 169 4-Methylpyrazole heme modification of, 281 as inhibitor, 421, 621, 627 hydroperoxo complex, 158, 159 0-Methylsterigmatocystin, 224 iron-aryl complex, 274, 275 N-Methylsulfonyl-12,12-dibromododec-11 -enamide, oxygen complexes, 156, 157 293 reaction with peroxides, 281, 154 N-Methylsulfonyl-6-(2- Myristic acid, 434 propargyloxyphenyl)hexanamide, 293, 294 Myzus nicotiana, 554 Methyl thieno[3.2.d][1.2.3]-thiadiazole-6-carboxylate, 283 Methyltrienolone, 351 NADP Sepharose chromatography, 227 Methylvinylmaleimide, 282 Naphthalene, 210,422 Methymycin, 600 dihydro-, 210 Metyrapone, 249, 250, 642 tetrahydro-, 33 Mice a-Naphthoflavone, 389, 398, 399, 402, 408, 409, 538 C57B1/6, 335 as allosteric effector, 427, 428 129SvJ, 538 as inhibitor, 428 Transgenic, 395, 416, 433, 435, 440, 455 2-Naphthylamine, 384 see Null mice 2-Naphthylhydrazine, 274 Miconazole, 250, 290, 291, 293, 592, 593 Narbomycin, 600 Microperoxidase, 154, 160 Naringenin,408,430, 571 Microsporum spp., 603 NcoR, 324,424 Midazolam, 386, 425, 426, 622, 629 Nectria haematococca, 603 cooperativity in metabolism of, 429 Nematode, sterol from diet, 590, 592 Mifepristone, 250, 259, 271, 622 Neomethycin, 600 680 Index

NF-IC, 449 NMR contd. Neopinone, 573 i^F, 203 Neurospora crassa, 589, 591, 602, 603 ligand binding, 25, 27, 64 NF-1,328 of metalloporphyrins, 17, 157, 267 NFKB, 442 of Pd/PdX complex, 136 Nicotiana tabacum, 554 Nomenclature, See P450 Nicotine NonO, 449 binding to P450 Norbomane, 3, 4, 8 oxidation of, 396, 403 exo-tetradeuterio-, 4 Nifedipine, 134, 386, 423,425, 426, 621, 628, 637 Norbornene NIH shift, 75, 202, 204 epoxidation, 17,26,269 Nikkomycin, 599 metalloporphyrin adduct, 269 Nitrene, 267 Norcarane, 11, 12,15,188 Nitric oxide, 2 Norepinephrine signaling, 538 as ligand, 51 Nomitrosonicotine, 384 P450 inhibition by, 248 Novobiocin, 599, 600 as product, 16, 571 NRl, 118, 120, 124, 125 Nitric oxide reductase , see CYP55A1 Nuclear receptors, 323, 325 Nitric oxide synthase, 1, 2 enhancer, 328 alternative electron acceptors, 120 phosphorylation, 324 and calmodulin, 16, 118, 120 Null mice, 380, 395, 396 domains, 118 acetyl CoA, 332, 334 structure, 16, 17,89 AHR, 338 mechanism, 16, 127, 150, 159 CAR, 330, 331 reactions, 16, 124 CYP1B1,395,396,400,401 redox properties, 125, 132 CYP2E1,395,419,420,422 spectroscopic properties, 156 cyp4al4, 543, 544 and tetrahydrobiopterin, 16 CYP7A1,439,440 Nitrite, 21 CYP11A1,446 /7-Nitroanisole, 194, 640 CYP19A 1,452 6-Nitrobenzo[a]pyrene, 401 CYP27A1,458 4-Nitrocatechol, 420 CYP27B 1,460 6-Nitrochrysene, 401 P450 reductase, 119, 120. 605 2-Nitrofluoranthene, 401 PPAR, 334, 335, 531, 539 3-Nitrofluoranthene, 401 PXR, 326, 327 Nitrogen oxidation Nystatin, 598, 599 N-dealkylation, 193, 194 methyl vs ethyl, 195 Obtusifoliol 14a-demethylation, 555, 558, 590 electron transfer in, 193 17-Octadecynoic acid, 294, 621, 630, 637 N-oxidation, 194 1-Octene, 33,268 /7-Nitrophenol, 420, 621 /ra/25-[l-2H]-, 198,268 1-Nitropyrene, 401 «-Octylamine, 646 2-Nitropyrene, 401 0-dealkylation, 193, 194 Nitroso complex, 266 17-ODYA, see 17-octadecynoic acid N-Nitrosobenzylmethylamine, 403 Okadaic acid, 329 N-Nitrosobutylamine, 403 Olanexidine, 214 N-Nitrosodimethylamine, 403, 621, 627, 636 Olanzapine, 399 N-Nitrosomethylphenylamine, 405 Oleandomycin, 599 N-Nitrosophenylmethylamine, 403 Oleic acid, 198 N-Nitrosodipropylamine, 403 Olefin oxidation, see Epoxidation N-Nitrosodiethylamine, 403, 405, 420 Oligomycin biosynthesis, 601 N-Nitrosonornicotine, 403 Oltipraz, 254 Nitrous oxide, 30 Omeprazole, 386, 394, 397, 399, 412, 621 NMR Ondansetron, 399 of adrenodoxin, 136 Orbital ofcytochromeP450 reductase, 120, 122 a2„, 50, 59, 62, 66, 77, 189 Index 681

Orbital contd. P450 contd. d, 48, 50 ordered solvent, 89 0RCA3, 569, 574 water content, 65 Org-30365, 289 branchpoints in catalysis, 156 Org-30958, 289 see Catalytic cycle Organic anion transporter, 327 conformational dynamics, 102, 106, 428, 429, 435 Oryza sativa, 554 cooperativity in, 394, 427-^29 Orphenadine, 406 distance from iron of oxidized atom, 100 Oryza sativa, 591 entry channel, 47, 65, 105, 108 Osmaronin, 565 expression of isoforms, 336, 392 Osmotic stress, 165, 586, 591 heme binding to protein, 435, 436 Ostrinia nubilatis, 568 human Ovariectomy, 351 identities, 378, 379 Oxidase, 151-153, 156, 158 classification, 380 Oxidation potential, see Redox potentials diseases, mutation based, 383 Oxidative stress, 422 inducers, major, 387 N-Oxides, see Oxygen donors liver content, 380-382, 385 reduction of, 120 relative importance of isoforms, 383, 386 2,3-Oxidosqualene cyclase, 590, 592 hydrogen bond network, 57, 63, 152, 164 Oximes, dehydration to nitriles, 228, 564 isomerase of hydroperoxides, 5 (19R)-10-oxiranylestr-4-ene-3,17-dione, 290 levels of, 381 7-Oxocholesterol, 439, 441 sex differences, 347 3-Oxodecalin-4-ene-10-carboxaldehyde, 222 mitochondrial, 379, 380, 419, 443, 444, 454, 456 7-Oxo-24,25-dihydrolanosterol, 291 nomenclature, 414, 554, 555, 586 2-Oxoglutarate dioxygenase, 567, 568 phylogenetic trees, 555. 591 Oxonium ion, 265 proteosomal degradation, 282 Oxygen, activation of proton delivery, 63, 152, 154, 155, 161, 162, 165, mechanism of, 149, 150 167, 169 oxygen-oxygen bond cleavage, 58, 59, 150, 154, 170 see Cysteine ligand homo-vs heterolytic, 151, 154, 155, 160, 439, 533 quantitation, 644 Oxygen donors rate limiting steps, 154, 427 acyl peroxide, 3, 23, 161 reduction potentials, 54, 134 alkyl peroxides, 3, 154, 185, 254, 263 resting state, calculations on, 51 unsuitability of, 221 RZ values, 645 hydrogen peroxide, 3, 5, 152, 221, 222 spectroscopic maxima, 644 hypochlorite, 23, 28 stoichiometry, P450 catalysis, 184 iodosobenzene, 3, 18, 28, 185, 194, 207, 221, 254, structure fold, overall, 87 439 see Substrate access channel reversibility of reaction, 17 topography, control of reaction, 73 N-oxides, 30-33, 197 P450Bi„j (CYP107H1), 135, 212, 213, 589 Oxone®, 32 P450^^ (CYPlOl), 585, 586, 595 periodate, 3, 32 active site, 46, 64 persulfide, 23 alternate oxygen donors, 3 product differences vs native system, 416 Asp251, 48, 63, 152, 164, 165, 167 Oxysterols, 458 Ala252, 163 Ozone layer, 30 autooxidation, 183 C357H, 183 P420 computational studies of mechanism, 69-71 formation, 285 D251N, 158 ligand in, 265 entry channel, 65, 136 quantitation, 645, 646 See Ferrous dioxygen complex spectrum, 645 ferryl species, 3, 46, 59, 60, 167 P450 fusion protein of, 138 active site Gin 360, 48, 60, 61 conserved residues, 598, 601 Gly248, 162 electrostatic potential, 89 Gly359, 48, 60 682 Index

P450cam (CYPlOl) contd. P450eryF (CYP107) contd. hydrogen bonding network, 57, 90, 152, 162, 167 computational studies, 55, 65 See Ferric hydroperoxo distal hydrogen donor, 89, 90 I-helix, 90 reaction catalyzed, 103 iron-aryl complex, 274 structure, 87-89, 101,428 Leu358, 48, 60 substrate-assisted mechanism, 90, 91, 163 ligand binding, 108, 109, 167 P450^^^(CYP55A1), 587 oxy-complex, 55, 89, 160, 167 ligand complexes, 169 oxygen activation, 55, 56 NADH binding to, 105 potassium binding site, 168 proton delivery, 169 protein radical of, 3 reduction of NO, 105, 169, 603 proton delivery, 48, 57, 152, 162, 165-169 structure of, 169, 183 putidaredoxin interaction with, 100, 135, 136 P450o,y3 rate limiting step, 136 vancomycin biosynthesis, 105 reaction catalyzed, 65, 103 X-ray structure, 206 spin state, 155 P450p^,^,599 solvent isotope effect, 56 P450j^P, 116 substrate binding, 63, 64, 155 P450^^^,5eeCYPllAl structure, 87-89, 101, 104, 108-110 P450^oy(SoyC), 135 Thr252, 6, 48, 55, 57, 152, 162-168, 185 P450^^^p(CYP108),598 Tyr96, 64, 65, 167, 168 structure, 183 see Uncoupling substrate, 595 water content of active site, 65, 71 P450™c. 599 P450BJ^.3 (CYP102), 585-587, 594, 601 Paclitaxel 6a-hydroxylation, 621, 625 active site, 537 Palmitic acid, 332, 434 aldehyde oxidation, 222, 283 Palmitoleic acid, 100, 105 domains, 118,596 Papaver somniferum, 554 electron transfer, internal, 132, 133 Paraciticein, 569 hydride transfer, 132 Parathion,250,251,395 reaction catalyzed, 11, 103 Parathyroid hormone, 454, 459, 538 redox properties, 125, 133 Parkinson's disease, 418 reductase domain interaction, 95, 96, 98, 115, 120, Paroxetine, 264, 265, 621, 627 130 Paxillin biosynthesis, 603 regulation of, 131 Pbx 1,449 salt bridges in, 92 PAR, see Pregnane X receptor structure, 87, 88, 106 PAS superfamily, 323, 324, 336 substrate PBREM, 405, 407 access channel, 65, 537 Penicillin biosynthesis, 585, 586, 587 specificity, 537, 540, 595, 596 Penicillium structure with, 100, 101, 105, 109, 131 chrysogenum, 586, 587 turnover number, 131 digitanum, 607 P450BSP italicum, 591 peroxide dependence, 99 paxilli, 603 fatty acid oxidation, 99 Pentafluorochlorobenzene, 203 structure, 99, 102 Pentalenolacton biosynthesis, 601 P450^^JCYP176A1) Pentobarbital metabohsm, 119 redox partners, 588 7-Pentoxyresorufin, 422, 634 cineol metabolism, 595 Perhexihne, 394 P450j^jj^, See Nitric oxide reductase Peroxidase P450EP„K axial ligand, 52, 89 function, 99 catalytic cycle, 151 reaction catalyzed, 103, 595 Compound I, 17, 150, 154 structure, 99, 100, 101, 104, 106 dioxygen bond cleavage, 154 P450eryF(CYP107) distal histidine, 154 binding two substrates, 428 electronic state, 52 cooperativity, 428 engineering of, 169 Index 683

Peroxidase contd. Phenylacetaldehyde, 28, 200 pKaofFe-OOH, 154 Phenylacetaldoxime, 555 reduction potentials, 89 Phenylacetate spin state, 52 growth on, 586 Peroxide shunt, 153, 156, 160, 184 2-hydroxylation, 586 Peroxisome proliferator activated receptor (PPAR), 323, Phenylacetylene, 257, 263, 269, 270, 271 331,545 Phenylalanine binding protein, 333 in biosynthesis, 561, 569 coregulators, 333, 335 N-hydroxylation of, 555 interaction with genes, 119 1 -Phenyl-1 -butanone, 200 ligands for, 332, 533 Phenylbutazone, 442 null mice, 334, 335 ^ra«5-l-Phenylbutene, 200 PPARa, 119,332,440,539 4-Phenyl-l-butyne, 271 PPARP, 332 Phenylcyclohexylamine, 260 PPAR7, 332,451 1 -(1 -Phenylcyclohexyl)-2,3-dihydro-4-pyridone, 259 species difference, 334 Phenylethyldiazene, 277 structure, 333 Phenethylisothiocyanate, 404 Peroxisome proliferation, 331, 332, 396, 434, 621 6-Phenyl-l-hexyne, 271 hormonal effects on, 354 6-Phenyl-2-hexyne, 271 regulation of P450 reductase, 119 Phenylhydrazine, 273, 274 Peroxygenase N-Phenylhydrazone, 273 activated species, 150 Phenylimidazole catal)^ic cycle, 151 P450 inhibition by, 249 Peroxynitrite, 23, 24, 442 structure of P450 complex, 100, 104 Persea americana (avocado), 556, 566 Phenylketene, 257 Petroselium crispum (parsley), 555 5-Phenyl-l-pentyne, 271 PGE2, 437, 534 2-Phenylphenanthridinone, 250 PGD2, 427 3-Phenylpropionaldehyde, 282, 283 PGE 1,427 1-Phenyl-1-propyne, 271 PGH synthase, see Prostaglandin H synthase Phenylpropanoid pathway, 570, 574 PGG2, 439 Phenytoin, 252, 386, 409, 443, 621 PGHj, 439 Phlobaphenes, 570 PGH2,441,442,531 Phorbol esters, 438, 440 P450 role in isomerization, 532 Phosphatidylcholine, 117, 541 hydroxylation of, 434, 534 Phosphatidylethanolamine, 541 PGJ2, 452 Phosphatidylinositol, 541 PGI2, 533 Phospholipases, 402, 535 Phanerochaete chrysosporium, 589, 591, 598, 602, 610 Photoacoustic calorimetry, 165 Pharmacogenetics, 387 Photochemical reduction, 157 Pharmacogenomics, 387 Photosystem I, 135 Pharmacokinetics, 347, 387, 393, 394, 409, 419, 424 Phthalate dioxygenase reductase, 138, 589 Pharmacophore models, 397, 399, 414-416, 455 Phylogenetic relationships, 555, 591 Phaseolus aureus (mung bean), 555 Phyllotreta nemorum, 562 Phenacetin, 204, 205, 394, 398^00, 621, 624, 633, 646 Phytoalexins, 553, 566, 568, 571, 603 Phencyclidine, 259, 260 Phytoanticipins, 553, 560 Phenelzine, 273, 274 Phytoattractants, 553 Phenformin, 418 Phytohormones, 554, 556, 558, 569, 574 Phenobarbital Piceatannol, 402 in arachidonate epoxidation, 539 Picia anomola, 591 as inducer, 402, 408, 412, 539, 621 Pikromycin, 599, 600 hormonal effects on, 354 Pimelic acid, 213 induction of P450 reductase, 119 Pinoline, 416 negative regulation of, 363 Piperonyl butoxide, 278, 642 receptor, 325 Pisatin, 603 responsive enhancer module, 328 Pisum sativum (snow pea), 571 Phenol, substituted, 185, 204 Pituitary, 350, 351 684 Index

Plasmalogens, 133 Pregnenolone contd. Pneumocystis carinii, 603 oxidation of, mechanism, 216, 217 Polychlorinated biphenyls, 336, 397, 399 ^^O studies in oxidation of, 215 Polycistric ovary syndrome, 450 Pregnenolone Polycyclic aromatic hydrocarbons 16a-carbonitrile, 324-327 binding to DNA, 207 6,16a-dimethyl, 325 fungal hydroxylation of, 602 Premarin®, 402 induction of P450, 335 Proanthocyanidins, 570 ionization potentials, 207 Prodrugs, 394 negative regulation of P450, 363 Progesterone, 415 oxidation of, 384,401 binding to CYP2C5, 108 Polyglandular syndrome, 446 and CAR activity, 329 Polymorphisms, human, 383, 387 21,21-dichloro-,255 see individual P450 isoforms 17a-hydroxy-, 449 influence on drug development, 389, 392, 394, 413 17-hydroxylation, 449 interindividual variation, 392 2a-hydroxylation, 640 single nucleotide (SNP), 387, 395, 402, 406, 409, 6p-hydroxylation, 637, 640 419, 423, 424, 433, 435, 442, 449, 461 15a-hydroxylation, 640 toxicities due to, 394, 396 16a-hydroxylation, 635, 640 ultrarapid metabolizers, 387, 414, 418 21-hydroxylation, 413, 453, 634, 637, 640 Polymorphonuclear leukocytes, 535 e«r-Progesterone, 450, 453 Popupus tremuloides (querken aspen), 555 9'-Propargyl abscisic acid, 259 Porphyria, 278 Propargylamine Porphyrin N-(2-heptyl)-, 259 binaphthyl, 9, 10,25,26 7V-(2-heptyl)-A^-methyl-, 259 biosynthesis, 278 Propene see Metalloporphyrin computational studies of oxidation, 68, 70, 71, 74, octamethyl, 62 77-79 "picnic-basket", 25, 26 in heme N-alkylation, 74, 268 polyfluorinated, 28, 29 Propentdyopents, 282 see Protoporphyrin IX Propionaldehyde, 221 saddling, 62 2-phenyl-, 221 me50-tetraaryl, 17, 18, 20, 29, 195 Propofol, 406 me^o-tetramethyl, 62 7-Propoxycoumarin, 422 "twin-coronet", 26, 27 2-«-Propyl-4-pentenoic acid, 208 Posaconazole, 605, 607 2-n-Propyl-2(£)-pentenoic acid, 209 Potential energy surfaces, 47 4-(l-Propynyl)biphenyl, 271 Potentiometry, 127, 128 10-(2-Propynyl)estr-4-ene-3,17-dione, 290 PPAR, See Peroxisome proliferator activated receptor 2-(l-Propynyl)naphthalene, 271 ^^P phosphate source, 157 2-(l-Propynyl)phenanthrene, 271, 398 Prandiol, 223 3-(l-Propynyl)phenanthrene, 271 Pregnancy, P450 induction in, 534 9-Propynylphenanthrene, 271 Pregnane X receptor (PXR), 323, 325 l-(l'-Propynyl)pyrene, 271, 398 in CYP3A induction, 324, 424, 425, 431, 433 Prostacyclin, 438, 441, 531 in CYP2B induction, 330, 405, 406 Prostacyclin synthase, see CYP8A1 in CYP2C induction, 408 Prostaglandin H synthase, 531 in CYP7A inducction, 440 EET oxidation, 533 null mice, 326, 327 model of, 26, 27 Pregn-4,20-diene-3-one, 634 N-dealkylation by, 195 5p-Pregnane-3,20-dione, CAR ligand, 329 reaction catalyzed, 540 Pregnenolone Prostaglandins 21-chloro-,255 biosynthesis, 1, 119 21,21-dichloro-,255 in inflammation, 332 17a-hydroxy-, 449 metabolism of, 294, 378, 437 hydroxylation, 441, 449 Prostanoids, metabolism of, 532, 533 Index 685

Protein kinase A, 445, 449, 453 Radical contd. Protein kinase C, 425, 453 lifetime, 9, 68, 187, 188 Proteosomal degradation, 282 probes, 9, 11,68-70 Proton inventory, 165 properties of in transition state, 72 Protoporphyrin IX rearrangement, 11, 15, 189 meso-Si\ky\-, 283 recombination, 5, 11, 12, 188 N-alkyl-, 278 spin trapping of, 194, 272, 273 N-(2-hydroxyalkyl)-, 277 trimethylsilyl, 286 N-(2-phenylethenyl)-, 277 tyrosine, 185, 186 N-(2-phenylethyl)-, 277 Radical cation N-vinyl-, 277 aromatic ring, 203, 207 4-(l-Propynyl)biphenyl, 199 porphyrin, 2, 3, 6, 11, 67, 153 Pseudohermaphroditism, 450 protein, 3 Pseudomona aeruginosa, 589 sulfur, 253 Pseudomonasputida, 3, 15, 87, 134, 585, 595 Radical clock, 9, 11, 68-70, 186-188 Psoralen, 187,223 effects of metals on, 14 Psoriasis, 460 Radiolysis,5, 157, 158, 167, 191 Puberty, 348, 349 Raloxifene, 253, 254 Putidaredoxin, 134, 595 Ralston metallidurans, 589 fusion protein of, 138 Random mutagenesis, 399 interaction with P450^^j^, 135, 136 Rapamycin, 599 interaction with putidaredoxin reductase, 98, 116 Rat mechanism, 136 Dahl Salt Resistant (DR), 543 structure of, 97, 99, 135 Dahl Salt Sensitive (DS), 543 Putidaredoxin reductase, 134, 595 dwarf, 355 dithiol/disulfide oxidoreductase activity, 138 Fischer 344, 363 fusion protein of, 137 Nude, 459 structure of, 97, 99, 116 Spontaneously Hypertensive (SHR), 543 Pyrene, 428 Sprague-Dawley, 363, 544 Pyridine, 249 Ravuconazole, 605, 607 1 -methyl-4-phenyl-1,2,3,4-tetrahydro-, 196 Reaction barriers, 47 4-aryl(alkyl)-l,4-dihydro-, 211 Rearrangements, oxidative 4-phenyl-^ra«5-1 -(2-phenylcyclopropyl)-1,2,3,6- see Acetylenes tetrahydro-, 197 see Aryl migration 17-(5-pyrimidyl)androsta-5,16-dien-3P-ol, 292 see Epoxidation 17-(3-pyridyl)androsta-5,16-dien-3(3-ol, 292 see NIH shift PXR, See Pregnane receptor see Radical clock Receptor Quadricyclane, 192 see Aryl hydrocarbon receptor Quercitin, 408 see Androstane receptor Quinidine see BRII receptor as allosteric effector, 428, 429 see Famesoid receptor as inhibitor, 254, 386, 389, 394, 417, 621, 626 see Glucocorticoid receptor as substrate, 423 see Growth hormone receptor Quinine, 426 see Nuclear receptors Quinone methide, 253 see Peroxisome proliferator activated receptor see Phenobarbital receptor R-76713,250,287,288 see Pregnane X receptor Radiation, 556 see Retinoid X receptor Radical see Vitamin D receptor alkoxy, 70,215,217 Redox potentials alkyl, 11, 12, 14, 189, 265, 272, 273, 275, 277, 280 P450 control of, 89, 131, 132 aryloxy, 26, 206, 207 Reductase partners, classification, 587-589 rer^butoxy, 8, 70, 189, 196 Regulation caged substrate radical, 8, 9, 14 see Diet, effects on P450 686 Index

Regulation contd. Sequence downregulation by cytokines, 388 homology model difficulties, 109 endocrine, 347, 541 structure models see Fasting CYP1A1,397 see Induction CYP1A2, 399 Renex 690 CYP1B1,402 Repeats, 323, 324, 336 CYP2A6, 404 Resonance Raman, 27, 156, 167 CYP2B6, 406 Response elements, 324, 326, 328, 337, 338, 397 CYP2C9,410 Resveratrol, 283, 402 CYP2C18,411 Reticuline, 205, 206, 571-573 CYP2C19,413 Retinoic acid, 119 CYP2D6,416 4-hydroxylation, 349, 379, 407, 409, 433, 455, 456 CYP2E 1,420 in P450 regulation, 440 CYP3A4, 427 Retinoid X receptor (RXR), 324, 328, 451, 454 CYP4A11,434 Rheumatoid arthritis, 450 CYP11B1,434 Rhizopus niger, 586, 587 CYP11B2,448 Rhodococcus sp., 588, 595, 596 CYP17A 1,450 Rhodotorula minuta, 226 CYP19A 1,452 Rhophalosiphum maydis, 568 CYP21A2,453 Rhapontigenin, 283, 284, 402, 632 SET mechanism, 195, 196, 226 Rickets, 459, 460 Sex hormone deficiencies, 383 Rifampicin, 386, 402, 407, 408, 412, 424, 433 Sex-linked differences Rifampin, 621 androgenic imprinting, 350 Ritonavir, 254, 415 in eicosanoid metabolism, 536 Rosiglitazone, 407 and growth hormone, 350-352 RU486, 325 in hepatic metabolism, 348 Ruthenium P450 levels in rat, 347, 353, 388, 537, 543, 544 P450gj^.3 modification, 96 specific forms, 348 porphyrin, 8, 12, 26, 28-33, 62, 73 Shear stress response element, 442 RZ values, 645 Sildenafil, 425 Simvastatin, desaturation of, 210 Saccharomyces cerevisiae, 585 Sinapoyl malate, 556 azole binding to, 605 Sinorhizobium meliloti, 589 in azole resistance, 608, 603, 605 SKF525-A, 278, 643 14a-demethylase, 558 Smoking, 395-397, 399, 400, 403, 404, 418 A^2-desaturation in, 210 SMRT, 324, 330, 333, 424 P450 enzymes, 589, 591, 601 Na+-K+-ATPase, 536, 538 P450 reduction in, 120, 605. 606 SOCS proteins, 361 Saccharum sp. (sugar cane) 560 Sodium transport, 541, 543 Salen metal complexes, 19 Solarium lycopersicon (potato), 560 Salt, 541, 543 Solvents Salt-inducible kinase (SIK), 445 see Ethanol Salt wasting syndrome, 453 induction by, 419 Salutaridine, 205, 206, 572, 573 inhibition of P450 activity, 389, 409 Saperconazole, 250 Soret maximum SCH66712, 283, 284, 417, 621, 627 alkyl or aryl-iron complex, 273, 275 Schizosacchawmyces pombe, 447, 589, 591, 601 carbene-iron complex, 264, 285 Scoulerine, 571,572 fifth iron ligand effect, 158, 248 Screening, high throughput, 133, 426 MI complex, 265 Secobarbital, 250, 256, 263, 267, 285, 634 red shift, 157 Secologanin, 224, 568, 569 reverse Type I, 248, 646 Sedormid, 256 split, 54, 156 Seminal vesicles, 534 Type I, 646 Senecionine, 384 Type II, 248, 249, 291, 292, 605, 646 Senescence, 349 Sorghum bicolor, 557, 558, 561, 573, 591 Index 687

SoyB, 135 Streptomyces Spl, 433, 442, 445, 449, 459, 461 avermitilis, 589, 596, 598 Sp3,433, 445, 499 CYPome, 600, 601 Sparteine, 383, 386,414 genome, 599 Spin densities, 61 coelicolor, 99, 589, 590, 594, 596, 600, 601 Spin echo envelope modulation (ESEEM), 51 CYP51 knockout of, 592 Spin state genome, 599 computation of, 47, 50, 51, 80 griseus, 135, 599 doublet, 51, 189,201 Streptomycete P450s, 599 quartet, 11, 12, 21, 49, 189, 190, 201 Strictosidine, 569 high, 48, 136 Styrene epoxidation, 185, 384, 420, 422 ligand effect on, 51, 61, 131 p-chloro-, 25, 28 low, 48, 136 electronic effects on, 28 relation to electron transfer, 131, 248 heme alkylation during, 267 sextet, 11,51 isotope effects on, 198 spectra associated with, 644 /?-methoxy-, 28 spin-orbit coupling, 9 /7-methyl-, 198 substrate binding effect on, 3 cw-|3-methyl, 25, 26 Spiro[2,4]octane, 188 /7-nitro-, 28 Spiro[2,5]octane, 12 /7-phenyl, 198 Spiromethylsulfone, 415 rearrangement during, 30, 200 Spironolactone, 253, 280, 281, 453 stereochemistry of, 27, 33, 65 7a-thio-, 450 Substrate Spirosulfonamide, 415 access channel, 47, 65, 102, 105, 108, 410, 537, 609 Spontaneously hypertensive rat, 543 exit channel, 47 Squalene, 1,590,592 Substrate binding, 183 SR12813, 325 channeling, in plant pathways, 563 SRC-1,324,330,333 contacting residues, 63 SREBP,461 control of redox/spin states, 3 Starvation, 331,537 determinants of, 63 Stat-3,451 location, 47 Stat-5a, 360 mobility in relation to, 5, 64 Stat-5b, 356-361, 364 of multiple substrates, 428 Sterigmatocystin, 211, 384 spectroscopic changes upon, 556, 646 Steroid water expulsion by, 71, 72 22-desaturation, 586, 592, 601-604 Substrates, functional markers, 621 6p-hydroxylation, 349, 555 Sulfaphenazole, 386, 407^10, 621, 626, 635 7a-hydroxylation, 349 Sulfenic acid, 253 I la-hydroxylation, 586, 587 Sulfinic acid, 253 II (3-hydroxylation, 586 Sulfite reductase, 96, 118 12-hydroxylase, 443 Sulfolobus 17a-hydroxylation, 379 solfataricus, 91, 100, 596, 601 23-hydroxylation, 555 tokodaii, 589 27-hydroxylation, 379 Sulfonic acid, 253 C4-methyl oxidase, 605 Sulforaphane, 254 5a-reductase, 349, 351, 364 Sulfur oxidation Steroidogenesis pathway, 444 S-dealkylation, 193 Steroidogenic factor 1 (SFl), 445^47, 449, S-oxidation, 76, 197 415,453 sulfur radical cation, 77, 197, 198 Sterol 11(3-/18-hydroxylase, see CYPl IB Superoxide Sterol 17a-hydroxylase/C 17-20 lyase, see CYPl7 dismutase, 197,258,282 Sterol 21-hydroxylase, see CYP21 reaction with P450, 157 Stigmasterol, 592 uncoupling product, 134 Stilbene, 33, 198, 570 Supersomes®, 252 St. John's wort, 394, 430 Surfactant, 285 Stopped flow studies, 20, 124, 126, 127, 132, 157 Sus scrofa, 591 688 Index

Sutherlandin, 565 Thermus thermophilus, 92, 596, 601 10-SUYS,293,294 Theophylline, 386, 398-400, 633 SXR, see Pregnane X receptor (205)-22-nor-22-Thiacholesterol,286 Sydnones, 275, 277 10-Thiiranylestr-4-ene-3,17-dione, 290 3-(2-phenylethyl)-4-methyl-, 277, 278 Thioester hydrolysis, 253 3-(2-phenylthioethyl)-4-methyl-, 278 Thiophene, 250,252,410 sulfoxide, 251 Tabersonine, 568, 569 Thiosteroids, 254 Tacrine 386, 399 2|3-Thiotestosterone, 637 Tamoxifen, 250, 262, 263, 351, 425, 452 6(3-Thiotestosterone, 636 TAO, see Troleandomycin Thioureas, 250 Tapesia Thlaspi arvense, 566 acuformis, 591 Threonine, conserved, 183, 185, 186, 192, 217 yallundae, 591 Thromboxane, 437-^39, 531 Taxiphyllin, 564 Thromboxane synthase, see CYP5A1 Taxol, 99, 378, 407, 408, 621, 625 Thujone, 210 TCDD, 336 Thyroid hormone as inducer, 335, 397, 538 in regulation of P450, 349, 362, 365, 440 as inhibitor, 399 in regulation of P450 reductase, 119, 365 in lowering P450 levels, 363 Thyroxine, 363 toxicity, 338 Ticlopidine, 252, 621, 625 Teasterone, 559, 560 Tienilic acid, 250, 251, 252, 410, 411, 621, 625 Tebuconazole, 593 Tirapazamine, 120 Tegafur, 403 Tolbutamide, 378, 386, 407-409, 411, 412, 621, 625 Temperature jump, 127 Toluene hydroxylation, 247 Terconazole, 250 20-(p-Tolyl)-5-pregnen-3p-ol, 212, 213 Terfenadine, 394, 426, 430 Tracazolate, 211 Terpineol, 595, 598 Transcription factors, 323 Testarone, 558 Transcriptome, 605 6-deoxy-, 558 Transgenic Testosterone mice, 395, 416, 433, 435, 440, 455 dehydrogenation of, 210 plants, 564 depletion by xenobiotics, 363 Transporters, 606 hormonal effects on P450, 350-351, 536 Cdrlp, 607, 608 2-hydroxy-, 635 Cdr2p, 607 6-hydroxy-, 210, 349, 378, 380, 425-428, MDR1,607,608 433, 434 role in drug removal, 392 7-hydroxy-, 210, 349 Tranylcypromine, 404, 621, 624 15-hydroxy, 349 TreP-132,445 16-hydroxy-,349, 635 Tretinoin, 622 17-hydroxylation, 413 Triacetyloleandomycin, see Troleandomycin in P450 regulation, 364, 449 Triazolam, 426 as substrate, 134, 164, 415, 452, 621, 622, 627, Triazole, in P450 inhibition 249 633-636, 640 Triethylenethiophosphoramide, 406 3,4,5,6-Tetrachlorocyclohexene, 186 Trifoliumpratense (red clover), 571 2,3,78-Tetrachlorodibenzo-p-dioxin, see TCDD Trifolium repens (white clover), 571 Tetracycline, 598 Trichloroacetaldehyde, 200 12-O-Tetradecanoylphorbol 13-acetate, 438, 502 Trichloroacetic acid, 332 Tetrahydrocannabinol, 261 1,1,1 -Trichloroethane, 420 2,3',4,5'-Tetramethoxystilbene, 285, 402, 633 Trichloroethylene, 200, 384, 420 Tetramethylpiperidine cleavage, 228, 229 Trichophyton reubrum, 603 TGF-Pj,451 Trichostatin A, 454 Thalidomide, 412 Triethylenethiophosphoramide, 621 Thaxtomin, 599, 600 Triglochin maritima, 557 Thebaine, 573 2,4,7-Trihydroxy-2H-l ,4-benzoxazin-3(4H)-one, 567 Thermal factors, in crystal structures, 65 Trimethoprim, 621, 625 ThermophiHc P450, 91 Trimethylamine, 195 Index

Trioxsalen, 261 Vancomycin biosynthesis, 206 Triticum aestivum (wheat), 555, 558, 564, 566, 567, 591 Vasoconstriction, 542 Troglitazone, 253, 254, 407 Vasodilation, 541, 542 Troleandomycin Vasopressin, 538 as inducer, 282 VDRE-1,454 as inhibitor, 265, 266, 282, 285, 425, 430, 433, 621, VDRE-2, 454 628, 637 Venturia nashicola, 591 modification of P450 compressibility, 429 Verapamil, 407 Try-P-1 (3-amino-1,4-dimethyl-5H-pyrido(4,5-Z>)indole, Vicia villosa, 571 365 Vigna radiata (mung bean), 560 Trypanosoma brucei, 591, 610 Vinblastin biosynthesis, 568, 569 Tryptamine, 404, 416, 568 Vincristine biosynthesis, 568, 569 Tryptophan as substrate, 555, 569, 574 Vindoline, 569 Tumor necrosis factor a (TNF), 419, 440, 451 Vinylbromide, 384, 420 Tumor promotion, 407 Vinyl carbamate, 384, 420 Type I spectrum, 646 Vinyl chloride, 384, 420, 422 Type I, reverse, spectrum, 248, 646 Vinyl fluoride, 268 Type 11 spectrum, 248, 249, 291, 292, 605, 646 (325)-Vinyllanost-8-en-3p,32-diol, 291 Tylosin, 599 18-Vinylprogesterone, 447 Typhasterol, 559, 560 Virilization, P450 link to, 383,454 Tyrosine Vitamin A deficiency, 364 />-hydroxy-, 562 Vitamin D, 440 iV-hydroxy-,561,562 deficiency, 455 to /7-hydroxyphenylacetaldoxime, 557 la-hydroxylation, 379, 459 kinase, 356-358 24-hydroxylation, 379 oligomerization by CYP57, 601 25-hydroxylation, 456, 457, 458 as precursor, 561, 564, 572 hypervitaminosis, P450 link to, 383 radical, 185, 186 manifold, overview of, 454 Two-state reactivity (TSR), 11, 66, 69, 73, 80, 188, 190, metabolism, 454 193,201,269 production in yeast, 586 receptor, 406, 425, 451, 454 Vitis vinifera, 574 Ubiquitin,282,419,425 VLDL, 541 10-UDYA, See 10-Undecynoic acid Voriconazole, 605, 606, 607 UGT1A6, 338 UGT85B 1,562-564 Warfarin Uncoupling, 156 dehydrogenation of, 210 by hydroperoxide dissociation, 5, 58, 161 as substrate, 386, 409, 410-412, 621, 632, 635, 640 cytochrome b5, effect of, 134 cooperativity in metabolism of, 429 oxidase pathway, 152, 156 polymorphism effect, 394, 410 phenomenon of, 152, 184 toxicity, 411 relation to structure, 154 Wound-induced response in plants, 553, 568, 569 and water access, 152, 163, 184 Wy 14643, in peroxisome proliferation, 332,434, 621 10-Undecynoic acid, 250, 256, 257, 263, 293, 621, 630, 637 XAP2, 336 10-Undecynyl sulfate, 293 XRE element, 397 USF 1,433 XREM, 433 Ustilago maydis, 603 Xylenes, 64, 202 XylM, 15, 16 Valeraldehyde, 221 Valeric acid, 226 Yarrowia lipolytica, 602 L-Valine, glucoside precursor, 561, 564 Yellow flourescent protein, 564 Vancomycin, 105 YYl transcription factor, 454 VanderWaals,46, 135 Lennard-Jones potential, 47 Zafirlukast, 280 Valproic acid desaturation, 208, 209, 280, 436 Zea mays (corn), 566, 567 3- and 4-hydroxy-, 209, 436 Zinc finger motif, 323