Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 65 No. 3 pp. 307ñ318, 2008 ISSN 0001-6837 Polish Pharmaceutical Society

CYTOCHROME P450 POLYMORPHISM ñ MOLECULAR, METABOLIC, AND PHARMACOGENETIC ASPECTS. II. PARTICIPATION OF CYP ISOENZYMES IN THE METABOLISM OF ENDOGENOUS SUBSTANCES AND DRUGS

PIOTR TOMASZEWSKI*, GRAØYNA KUBIAK-TOMASZEWSKA and JAN PACHECKA

Department of Biochemistry and Clinical Chemistry, Pharmaceutical Faculty, Medical University of Warsaw 1 Banacha str., 02-097 Warsaw, Poland

Abstract: In the human organism 58 cytochrome P450 (CYP) isoenzymes belonging to 18 families have been described. These hemoproteins, with enzymatic activity characteristic for monooxygenases, show a broad affin- ity for chemically differentiated endo- or exogenous compounds, including drugs. CYP isoenzymes participate in metabolic pathways important for proper physiological functioning of the human organism, i.e.: cholesterol, bile acid and oxysterol biosynthesis; metabolism of fatty acids, prostaglandins, prostacyclins, leukotrienes, steroid hormones, ketone bodies, vitamines A and D. CYP isoenzymes participate in the metabolism of over 80% of drugs and other xenobiotic substances which can be present in the human organism. Differences in molecular structure and kinetics of conformational changes of particular isoenzymes of CYP superfamily monooxygenases on the one hand determine their affinity direction for chemically differentiated groups of com- pounds susceptible to oxidation, on the other hand determine the mechanism and position of the oxidative change of their molecules. Drugs and their metabolites and other endogenous and xenobiotic compounds may be acting not only as substrates, but also as competitive and non- competitive inhibitors, suicide inhibitors and inducers of CYP isoenzymes as well as repressors of CYP genes. These relationships are the metabolic basis of numerous multidirectional interactions between drugs, drug metabolites, food components, stimulants, envi- ronmental toxins and metabolites of these xenobiotics.

Keywords: CYP isoenzymes, drug biotransformation, CYP substrates, CYP inhibitors, CYP inducers, repres- sors of CYP genes.

Abbreviations: ADH ñ alcohol dehydrogenases: NAD-dependent (EC 1.1.1.1) and NADP-dependent (EC 1.1.2); ALDH ñ aldehyde dehydrogenases: NAD-dependent (EC 1.2.1.3), NADP-dependent (EC 1.2.1.5); AhR ñ nuclear aromatic hydrocarbon receptor; CAR ñ nuclear constitutive androstane receptor; CDCA ñ chenodeoxycholic acid; COX ñ cyclooxygenases (EC 1.14.99.1); CYP ñ cytochrome P450; DCA ñ deoxy- cholic acid; ER ñ endoplasmic reticulum; FMO ñ flavin monooxygenases (EC 1.14.13.-); FXR ñ nuclear farnezoid Xreceptor; LCA ñ litocholic acid; MAO ñ monoamine oxidases (EC 1.4.3.4, EC 1.4.3.6); PAH ñ polycyclic aromatic hyrbocarbons; PPARa ñ peroxisome proliferator-activated receptor a; PXR ñ nuclear pregnane Xreceptor TCDCA ñ taurochenodeoxycholic acid; XO ñ xanthine oxidase (EC 1.17.3.2).

CYP molecular species (Table 1), designated with a number after the abbrevi- Several hundred CYP isoenzymes have been ation CYP (e.g. CYP1) and 41 subfamilies, designat- identified and described in living organisms (1). ed by a letter in the next position of the abbreviation Many of them occur in several or even in several (e.g. CYP1A). The basis for the classification of CYP dozen isoforms, which generally are the results of isoenzymes is the amino acid sequence similarity of genetic polymorphism, i.e. the occurrence of differ- over 40% in families and over 55% in subfamilies (1). entiated CYP gene alleles formed through point Participation of CYP isoenzymes in endoge- mutations of precursor genes (2, 3). In some cases nous substance metabolism CYP molecular species arise as the result of differ- CYP isoenzymes participate in metabolic pathways entiated mechanisms of transcription initiation of important for proper physiological functioning of one gene, common for all these species (4, 5). the human organism: So far in the human organism 58 CYP isoen- ñ cholesterol biosynthesis: CYP51A1, CYP20A1 zymes belonging to 18 families have been described (1, 6, 7);

* Corresponding author: e-mail: [email protected]

307 308 PIOTR TOMASZEWSKI et al. Tissue distribution testis, prostate, ovary and lung parenchyma cells; lymphocytes; hepatocytes spleen parenchyma cells; choroid trachea and cochlear epithelial cells hepatocytes; lung parenchyma cells; mammary gland epithelial cells; cerebral neurons trachea, nasal cavity, urinary tract, uterus and mammary gland epithelial cells; cerebral neurons hepatocytes; lung parenchyma cells; trachea epithelial cells; small intestinal mucosal cells pancreas parenchyma cells hepatocytes; renal, lung, testis, ovary, spleen, and and cardiomyocytes cardiomyocytes; intestinal mucosal cells; renal parenchyma cells; hepatocytes small intestinal and stomach mucosal cells; trachea epithelial cells; spleen and lung parenchyma cells cerebellum neurons, thymus and parathyroid parenchyma cells, living epidermis cells lung parenchyma cells; adrenal medulla esophagus and stomach mucosal cells R hepatocytes; small intestinal and tongue mucosal cells; Cellular localization (kDa) acid residues* weight * amino Molecular Number of isoforms Number of CYP2C8CYP2C9 9 29 55.8 55.6 490 490 ER ER hepatocytes hepatocytes CYP1A1 9CYP2A6 58.2 20 512 56.0 494 ER mammary gland and uterus epithelial cells; ER CYP2C18CYP2C19 1 15 55.6 490 55.9 E 490 ER hepatocytes CYP2A13 9 56.7 494 ER hepatocytes; lung, testis and prostate parenchyma cells; CYP2J CYP2J2 10 57.7 502 ER CYP2F CYP2F1 1 55.5 491 ER lung parenchyma and epithelial cells CYP2S CYP2S1 2 58.0 504 ER CYP2E CYP2E1 4 56.0 493 ER pancreas parenchyma cells; skeletal muscle myocytes CYP1B CYP1B1 16CYP2B 60.8 CYP2B6CYP2C 28 543 56.3 ER CYP2R 491 CYP2R1 1 ER 57.3 501 ER neurons; stomach and oral cavity mucosal cells CYP1A CYP2A CYP2A7 4 42.0 443 ER hepatocytes CYP2U CYP2U1 1 62.0 544 ER CYP2W CYP2W1 1 53.8 490 ER CYP1 CYP1A2 16 5 8.3 515 ER hepatocytes; lung parenchyma cells CYP2 CYP2D CYP2D6 44 55.8 497 ER hepatocytes Family Subfamily Isoenzyme Table 1a. Human CYP isoenzymes ñ part I (1, 2, 6, 17, 34, 35, 36, 37). Cytochrome P450 polymorphism ñ molecular, metabolic and pharmacogenetic aspects. II... 309 Tissue distribution neurons; lung, spleen and placenta parenchyma cells; pharyngeal mucosal cells hepatocytes; renal parenchyma cells; small intestinal mucosal cells bone marrow cells; granuloctes; esophagus, larynx and large intestinal mucosal cells spermatic duct epithelial cells; prostate parenchyma hepatocytes hepatocytes; renal parenchyma cells; skeletal muscle myocytes and cardiomyocytes cardiomyocytes; renal parenchyma cells; intestinal mucosal cells hepatocytes; renal, thyroid, lung and pancreas parenchyma cells; cochlear epithelial endothelial lymphocytes; skeletal muscle myocytes and cardiomyocytes hepatocytes; hippocampus and cerebellum neurons; prostate and placenta parenchyma cells hepatocytes; mammary gland epithelial cells; placenta and lung parenchyma cells bone marrow cells; macrophages and trombocytes; lung, renal and spleen parenchyma cells hepatocytes; renal and prostate parenchyma cells; intestinal mucosal cells hepatocytes; renal and spleen parenchyma cells; cardiomyocytes; intestinal mucosal cells prostate, testis, renal and pancreas parenchyma cells; hepatocytes; skeletal muscle myocytes Cellular localization (kDa) acid residues* weight * amino Molecular Number of isoforms Number of CYP4F2CYP4F3CYP4F8 1 1 1 59.9 59.8 60.0 520 520 590 ER (M ?) ER (M ?) ER (M ?) CYP3A7 3 57.5 503 ER (M ?) CYP3A3CYP3A4 1 18 57.4 57.3 502 503 ER ER hepatocytes CYP4F12 1 57.0 524 ER, (M ?) CYP4F11CYP4F22 1 1 57.0 62.0 524 531 ER, (M ?) ER cerebral neurons; larynx mucosal cells CYP3A43CYP4A11CYP4A22 3 2 1 55.0 59.3 59.4 504 519 519 ER ER (M ?) ER hepatocytes; renal parenchyma cells hepatocytes CYP4F CYP4Z CYP4Z1 1 59.0 505 ER CYP4B CYP4B1 6 59.0 511 ER CYP4X CYP4X1 1 58.9 509 ER cochlear, mammary gland and trachea epithelial cells; CYP4V CYP4V2 1 60.6 525 ER CYP4A CYP4 CYP5 CYP5A CYP5A1 9 60.0 534 ER CYP3 CYP3A CYP3A5 7 57.1 502 ER (M ?) hepatocytes; prostate parenchyma cells Family Subfamily Isoenzyme Table 1b. Human CYP isoenzymes ñ part I (1, 2, 6, 17, 34, 35, 36, 37). 310 PIOTR TOMASZEWSKI et al. Tissue distribution hepatocytes; cerebral neurons; cardiomyocytes; adrenal medulla cells cerebral neurons; retina cells; lung and testis parenchyma cells; living epidermis cells retina cells; neurons; lung and testis parenchyma cells; living epidermis cells hepatocytes; renal and lung parenchyma cells; small intestinal mucosal cells; living epidermis neurons hepatocytes; renal, lung, testis, ovary, prostate and adrenal cortex parenchyma cells hepatocytes, stomach and intestinal mucosal cells, cerebral neurons and astrocytes, skeletal muscle myocytes; renal, testis, ovary and prostate parenchyma cells; esophagus, uterus and cochlear epithelial cells; skeletal muscle myocytes and cardiomyocytes endothelial cells; ovary, testis, placenta and adrenal cortex parenchyma cells eight and number of amino acid residues in the polypeptide chain wild-type Cellular localization (kDa) acidresidues* weight * amino Molecular Number of isoforms Number of CYP11B1CYP11B2 1 1 57.5 57.6 503 503 M M adrenal cortex parenchyma cells; mammary gland epithelial cells adrenal cortex parenchyma cells CYP7B CYP7B1CYP8B 1 CYP8B1 58.2 1 506 58.1 501 M ER hepatocytes CYP7A CYP7A1 1 57.7 504 ER hepatocytes CYP8A CYP8A1 4 57.1 500 ER lung, ovary and prostate parenchyma cells; CYP26C CYP26C1CYP27BCYP27C CYP27B1 2 CYP27C1 1 57.1 1 56.0 522 60.2 508 ER 531 M M renal tubular epithelial cells; living epidermis cells hepatocytes, renal and pancreas parenchyma cells CYP11B CYP27A CYP27A1 1 60.2 531 M CYP26A CYP26A1 1 56.0 497 ER, (M ?) CYP11A CYP11A1 1 60.2 521 M CYP7 CYP8 Family Subfamily Isoenzyme CYP17CYP19 CYP17ACYP20 CYP19ACYP21 CYP17A1 CYP20ACYP24 CYP19A1 CYP21A CYP24A CYP20A1 CYP21A2 1 CYP24A1 1 1 85 57.4 1 57.0 47.7 55.9 508 58.9 502 416 494 ER, M 514 ER, M ER adrenal cortex, ovary and testis parenchyma cells ER ovary and placenta parenchyma cells; cerebral neurons M placenta parenchyma cells adrenal cortex parenchyma cells hepatocytes CYP26 CYP26B CYP26B1CYP27 1 57.5 512 ER CYP39CYP46 CYP39ACYP51 CYP46A CYP39A1 CYP51A CYP46A1 CYP51A1 1 1 1 54.1 56.8 56.8 469 500 503 ER ER, (M ?) ER, (M ?) cerebral neurons hepatocytes CYP11 Table 1b cont. Abbreviations in Tables 1a and 1b: ER ñ endoplasmic reticulum, M mitochondrion, ? data required verification. * Molecular w protein. Cytochrome P450 polymorphism ñ molecular, metabolic and pharmacogenetic aspects. II... 311 , ciprofloxacin , NO quinidine, Inhibitors cimetidine -naphthoflavone , α which act as competitive inhibitors). quercetin (e.g. from grapefruit juice), in the column Ñxenobiotic substratesî, (except of alternative substrates mentioned omeprazole phenobarbital ketoconazole, nd xenobiotic substrates, inducers, inhibitors and repressors (1, 2, 8, 9, 15, , -naphthoflavone, β dioxins (e.g. TCDD), (components of wood smoke), dioxins (e.g. TCDD), nicotine, dexamethasone PAH (e.g.. from tobacco smoke), PAH (e.g.. from tobacco smoke), benzopyrene, cresol, acrolein, benzene , phenacetin, , ñ PAH glucosinates of broccoli aflatoxin B1 glucobrassicin etc.) taxol, torsemide, phenobarbital, rifampicin including drugs Inducers zileuton, zolmitriptan (bolded and italicized) amitriptyline, caffeine, aflatoxin B1, coumarins, verapamil, (R)-warfarin, rifampicin, ritonavir, mephenytoin, repaglinide, gemfibrozil, montelukast, pioglitazone, rosiglitazone, trimethoprim, (e.g.. from tobacco smoke) (components of wood smoke), iphosphamide, methadone rifampicin, vit.D amodiaquine, cerivastatin (e.g.. from tobacco smoke), and brussels sprouts (glucoraphanin, clozapine, cyclobenzapirene, riluzole, ropivacaine, tacrine, oxcarbazepine, phenobarbital, methoxsalen, mibefradil, ticlopidine bupropion, cyclophosphamide, cyclophosphamide, phenobarbital, thiotepa, ticlopidine, benzopyrene, 7-ethoxycoumarin caffeine, pethidine caffeine, progesterone and other steroids, chlordiazepoxide, clomipramine, polycyclic aromatic hydrocarbons 3-methyl-cholanthrene, diazepam, estradiol, fluvoxamine, cyclophosphamide, iphosphamide, amoxifen, theophylline, tizanidine, phenytoin, primidone, naproxen, olanzepine, ondansetron, insulin, lamotrigine, lansoprazole, amiodarone haloperidol, imipramine, mexiletine, carbamazepine, hyperforin, paracetamol, phenacetin, propranolol, modafinil, nafcillin, omeprazole, furafylline, interferons, isoniazid, acid, steroids, steroids, steroids, estradiol and other substrates arachidonic fatty acids. fatty acids, fatty acids. fatty acids. polycyclic aromatic hydrocarbons ñ PAH benzopyrene, cresol, acrolein, benzene Endogenous - Coumarin hydroxylase EC number hydroxylase, EC 1.14.14.1 EC 1.14.14.1 4-hydroxylase 7-hydroxylase nicotine, nitrosamines NO E.C. 1.14.14.1 steroids. E.C. 1.14.14.1 retinoic acid. S-mephenytoin Aryl hydrocarbon Aryl hydrocarbon Common enzyme Xenobiotic substrates and repressors CYP2B6 CYP2A6 CYP2C8 CYP1A2 CYP1A1 able 2a. CYP isoenzymes belonging to CYP1 and CYP2 families participating in drug metabolism with their respective endogenous a Iso-enzyme name(s) T 16, 17, 19, 23, 26, 36, 38). 312 PIOTR TOMASZEWSKI et al. cocaine, NO NO Inhibitors fluconazole methadone, mibefradil, midodrine, which act as competitive inhibitors). in the column Ñxenobiotic substratesî, fluoxetine, fluvoxamine, ketoconazole, (except of alternative substrates mentioned , rifampicin probenicid, ritonavir, norethindrone , , - * pesticides including drugs Inducers (bolded and italicized) diazepam, mephenytoin, (S)-warfarin, zidovudine (R)-warfarin, zidovudine alprenolol, amphetamine, amiodarone, bupropion, celecoxib, hexobarbital, imipramine, amitriptyline, aripiprazole, cimetidine, citalopram, clemastine, omeprazole, phenobarbital lansoprazole, mephenytoin, carbamazepine pantoprazole, phenobarbital, ticlopidine, topiramate indomethacin, clomipramine, chloramphenicol, cimetidine, felbamate, mephobarbital, moclobemide, phenobarbital, phenytoin, modafinil, oxcarbazepine, paroxetine, cyclophosphamide, diazepam, desipramine, dexfenfluramine, levomepromazine, metoclopramide, glipizide, ibuprofen, irbesartan, hyperforin, carbamazepine, lansoprazole, lovastatin, miconazole, dextromethorphan, doxylamine, duloxetine, encainide, flecainide, moclobemide, nefazodone, quinidine, amitriptyline, celecoxib, dapsone, diclofenac, dicumarol, fluoxetine, amiodarone, cimetidine, fenofibrate, chlorphenamine, chlorpromazine, doxorubicin, escitalopram, atomoxetine, bufuralol, carvedilol, diphenhydramine, doxepin, tamoxifen, tolbutamide, torsemide, zafirlukast, nelfinavir, nilutamide, omeprazole,nelfinavir, prednisone lornoxicam, losartan, mephenytoin, rifampicin, phenobarbital, omeprazole, phenylbutazone, probenicid, pitavastatin, rosiglitazone, suprofen teniposide, ticlopidine, voriconazole, phenytoin, primidone, progesterone, proguanil, propranolol, rabeprazole, fluoxetine, fluvoxamine, haloperidol, sertraline, terbinafine, ranitidine, ritonavir, phenobarbital, phenytoin, piroxicam, sulfamethoxazole, sulfaphenazole, temazepam, teniposide, valproic acid, clomipramine, codeine, debrisoquine, halofentrine, hydroxyzine, ketoconazole, halothane, hydrocodone, imipramine, ticlopidine, tripelennamine, meloxicam, (S)-naproxen, paroxetine, secobarbital, sertraline, ritonavir, fluvastatin, glibenclamide, glimepiride, fluconazole, fluvoxamine, isoniazid, amitriptyline, carisoprodol, citalopram, - ) S /( (R) limonene substrates Endogenous )-limonene )-limonene )-limonene R S S EC number ( ( ( Debrisoquine 4-hydroxylase steroids E.C. 1.14.14.1 E.C. 1.14.13.80 E.C. 1.14.13.48 E.C. 1.14.13.49 Common enzyme Xenobiotic substrates and repressors 6-monooxygenase 6-monooxygenase 7-monooxygenase CYP2C9 CYP2D6 CYP2C18 CYP2C19 able 2a cont. Iso-enzyme name(s) T Cytochrome P450 polymorphism ñ molecular, metabolic and pharmacogenetic aspects. II... 313 , , cimetidine Inhibitors diethyldithiocarbamate which act as competitive inhibitors). in the column Ñxenobiotic substratesî, (except of alternative substrates mentioned , bergamottin, bergapten, rifampicin (1.3-fold induction) (41), dexamethasone (42), modafinil in high ethanol, acetone 6í,7;-dihydroxybergamottin kaempferol theophylline, including drugs Inducers (bolded and italicized) phenacetin, phenformin, paracetamol, sevoflurane, clofibrat, isoniazid nortriptyline, ondansetron, vincristine, zuclopenthixol, isoflurane, methoxyflurane, disulfiram, isoniazid, dapson, enflurane, halothane, tramadol, timolol, venlafaxine, acetaminophen, chlorzoxazone, methoxyamphetamine, mianserin, sparteine, tamoxifen, thioridazine, MDMA (ecstasy),7-ethoxycoumarin omeprazole, opipramol, oxycodone, propranolol, risperidone, selegiline, minaprine, (S)-metoprolol, nebivolol, N,N-dimethylformamide, nitrosamines paroxetine, perphenazine, perhexiline lidocaine, metoclopramide, mexiletine, promazine promethazine, propafenone, substrates Endogenous studies (38), methylphenidate (43) donít have any clinical significance. in vitro Acetol acetone, Acetone EC number E.C. 1.14.14.1 ethanol, benzene, aniline, (e.g. from grapefruit juice) monooxygenase acetol. monooxygenase Common enzyme Xenobiotic substrates and repressors CYP2E1 concentrations (i.e.1000 mM) in able 2a cont. Iso-enzyme name(s) T * Induction of CYP2D6 by xenobiotics remains controversial (39) and often questioned (18, 28, 40). Weak induction by: 314 PIOTR TOMASZEWSKI et al. Inhibitors naringenin carbamazepine bergapten, naringin, estradiol, bergamottin, pregnandiol, pregnantriol, (e.g. from grapefruit juice) diethyldithiocarbamate, NO progesterone, pregnenolone, which act as competitive inhibitors). in the column Ñxenobiotic substratesî, (except of alternative substrates mentioned , CDCA estradiol, pesticides testosterone, LCA, androstendione, glucocorticoids, glucocorticoids, tic substrates, inducers, inhibitors and repressors (1, 2, 8, 9, 15-17, CYP3A4 cocaine progesterone, CYP3A4 CYP3A4 same drugs like nifedipine including drugs Inducers except quinidine (bolded and italicized) subfamily isoenzymes) same drugs like same drugs like ziprasidone, zolpidem, verapamil, vincristine, zaleplon, (affinity lower than other CYP3A methadone, metronidazole, midazolam, phenytoin, mibefradil, voriconazole, ivabradine, ketoconazole, lercanidipine, omeprazole, norfloxacin, norfluoxetine, digoxin, diltiazem, docetaxel, domperidone, griseofulvine, ciprofloxacin, delaviridine, finasteride, fluoxetine, gleevec, haloperidol, modafinil, imatinib, itraconazole, saquinavir, salmeterol, sildenafil, simvastatin,saquinavir, rifampicin, dexamethasone, dextromethorphan, diazepam, erythromycin, chloramphenicol, cimetidine, etoposid, ethynylestradiol, felodipine, fentanyl, lansoprazole, fluvoxamine, gestodene, levonorgestrel, lidocaine, loratadine, lovastatin, oxcarbazepine, norfloxacin, norfluoxetine, mifepristone, nateglinide, nelfinavir, nifedipine,mifepristone, nateglinide, nelfinavir, phenobarbital, eplerenone, ergotamine, erythromycin, estradiol, hyperforin, efavirenz, fluconazole, halothane, hydrocortisone, indinavir, irinotecan,halothane, hydrocortisone, indinavir, nevirapine, nefazodone, nevirapine, alfentanyl, alprazolam, amiodarone, amlodipine, carbamazepine, clarithromycin, codeine cyclosporine A, dapsone,clarithromycin, codeine cyclosporine efavirenz, atorvastatin, buspirone, caffeine, carbamazepine,atorvastatin, buspirone, caffeine, delavirdine, terfenidine, testosterone, theophylline, trazodone, troglitazone, triazolam, vit D, valproate, warfarin, venlafaxine, sufentanyl, tacrolimus (FK506), taxol, tamoxifen, topirimate, amitryptyline, aprepitant, aripiprazole, astemizole, cyclophosphamide, paracetamol, pimozide, propranolol, progesterone, prednisone, nisoldipine, nitrendipine, ondansetron, omeprazole, pioglitazone, cerivastatin, chlorpheniramine, cilostazol, cisapride, dexamethasone, quetiapine, quinidine, quinine, risperidone, ritonavir, rifabutin, substrates fatty acids, testosterone testosterone, aflatoxin B1 and androsterone subfamily isoenzymes) Endogenous other CYP3A LCA, TCDCA, (affinity lower than subfamily isoenzymes) - - - cholate testosterone, Steroid progesterone, Quinine Enzyme Xenobiotic substrates and repressors -hydroxylase androstendione, Vitamin D EC number α E.C. 1.14.14.- steroids. pregnenolone E.C. 1.14.14.1 E.C. 1.14.14.1 3-sulfodehydroepi- (affinity lower than other CYP3A E.C. 1.14.14.1 subfamily isoenzymes) E. C. 1.14.13.- 25-hydroxylase 6 monooxygenase, testosterone, E. C. 1.14.13.97 estradiol E. C. 1.14.13.67 3-monooxygenase Taurochenodeoxy- progesterone, Nifedipine oxidase androstendione (affinity lower than other CYP3A Nifedipine oxidase CYP3A7 CYP3A5 CYP3A4 CYP3A3 CYP3A43 Iso-enzyme name(s) Table 2b. CYP isoenzymes belonging to CYP3 family participating in drug metabolism with their respective endogenous and xenobio 19, 23, 26, 36, 38). Cytochrome P450 polymorphism ñ molecular, metabolic and pharmacogenetic aspects. II... 315

ñ bile acid biosynthesis: CYP7A1, CYP7B1, ñ epoxidation (e.g. carbamazepine by CYP3A4); CYP8B1, CYP27A1, CYP3A4, CYP39A1 (4, 8, 9, ñ alcohol and aldehyde oxidation (e.g. metronida- 10); zole by CYP3A4); ñ steroid hormone metabolism: CYP1A2, CYP2C9, ñ N-oxidation (e.g. mexiletine by CYP2D6); CYP2C18, CYP2C19, CYP3A4, CYP3A5, ñ S-oxidation (e.g. thioridazine by CYP2D6, CYP3A7, CYP3A43, CYP11A1, CYP11B1, omeprazole by CYP3A4); CYP11B2, CYP17A1, CYP19A1, CYP21A2 (1, 6); ñ oxidative O-dealkylation (e.g. codeine by ñ metabolism of fatty acids, prostaglandins, prosta- CYP2D6); cyclins and leukotrienes: CYP2C8, CYP2J2, ñ oxidative N-dealkylation (e.g. diazepam by CYP2U1, CYP2W1, CYP4A11, CYP4A22, CYP2C19, mianserin by CYP3A4); CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, ñ oxidative S-dealkylation (e.g. 6-methylthiopurine CYP4F22, CYP4X1, CYP5A1, CYP8A1, by CYP2D6); CYP20A1 (1, 6, 11); ñ oxidative deamination (e.g. amphetamine by ñ oxysterol biosynthesis: CYP7A1, CYP27A1, CYP2D6); CYP39A1, CYP46A1 (4, 6); ñ oxidative denitrification (e.g. aminophenazone by ñ ketone body metabolism: CYP2E1 (6, 12); CYP3A4); ñ vitamin A metabolism: CYP2C8, CYP26A1, ñ oxidative desulfurylation (e.g. thiopental by CYP26B1, CYP26C1 (2, 13); CYP2D6); ñ vitamin D metabolism: CYP2R1, CYP3A4, ñ oxidative dehalogenization (e.g. halothane by CYP24A1, CYP27A1, CYP27B1, CYP27C1 (6, CYP2E1); 14). ñ oxidative cyclization (e.g. piroxicam by CYP2C9); Participation of CYP isoenzymes in drug metabo- ñ aromatization of alicyclic compounds (e.g. lism nifedipine by CYP3A4 or CYP3A3); CYP isoenzymes participate in the metabolism ñ oxidative decyclization (e.g. alprazolam by of over 80% of drugs and other xenobiotic sub- CYP3A4). stances which can be present in the human organ- Differences in molecular structure and kinet- ism. Among the three basic mechanisms of phase I ics of conformational changes of particular isoen- of drug biotransformation i.e. oxidation, reduction zymes of CYP superfamily monooxygenases deter- and hydrolysis, oxidative changes are the most fre- mine their affinity direction for chemically differ- quent. The main catalysts in oxidative changes of entiated groups of substances susceptible to oxida- most xenobiotics, including drugs, are monooxyge- tion. The differences in the structure of active cen- nases from the CYP superfamily (15). The remain- ters on the one hand determine the ability to inter- ing enzymes catalyzing oxidation reactions e.g. act with substrates with defined chemical structure flavin monooxygenases ñ FMO (EC 1.14.13.-), characteristics and on the other hand determine the alcohol dehydrogenases ñ ADH (EC 1.1.1.1, EC mechanism and position of the oxidative change of 1.1.1.2) and aldehyde dehydrogenases ñ ALDH (EC their molecules. Thus a defined xenobiotic (e.g. a 1.2.1.3, EC 1.2.1.5), monoamine oxidases ñ MAO drug) may be biotransformed only by some, and (EC 1.4.3.4, EC 1.4.3.6), xanthine oxidase ñ XO sometimes just by one defined variant among all (EC 1.17.3.2), cyclooxygenases ñ COX (EC isoenzymatic CYP variants. The frequently possi- 1.14.99.1); are only a complement of the palette of ble monooxygenation of the same substrate by 2-4 enzymatic possibilities of xenobiotic oxidation, as different CYP isoenzymes in general concerns dif- they show affinity for only a fairly narrow group of ferent positions and groups in the chemical struc- substrates with strictly defined chemical structure ture of the molecule, giving in effect a differentia- targets (6, 16). tion of phase I biotransformation metabolites of the Monooxygenases from the CYP superfamily same compound (drug or other xenobiotic). For show a broad affinity for chemically differentiated example (15, 17): compounds susceptible to oxidation. Depending on ñ diazepam with participation of CYP2C19 under- the chemical structure of the substrates their goes oxidative N1-demethylation, whereas with monooxygenation may lead to (15, 16): CYP3A4 hydroxylation in position 3 takes place; ñ C-oxidation: ñ codeine undergoes oxidative O-demethylation by ñ hydroxylation of aromatic (e.g. propranolol by CYP2D6, whereas with participation of CYP3A4 CYP1A2) and aliphatic (e.g. valproate by CYP3A4) oxidative N-demethylation takes place. compounds; 316 PIOTR TOMASZEWSKI et al.

Among the 58 CYP isoenzymes identified in the logic of competitive inhibition, the decrease of the human organism (Table 1) the following have the biotransformation effectiveness of substrate ÑAî the greatest share in drug metabolism (1, 15, 17, 18): by a given CYP isoenzyme is proportional to the CYP3A4ñ making up 18-35% of the total monooxy- ratio of the concentrations of substrate ÑBî playing genase pool from the CYP superfamily in liver the role of an inhibitor and substance ÑAî, which is parenchyma and oxidizing approximately 50% of all considered to be the proper substrate, and the ratio oxidatively biotransformed drugs; of the affinity of a given CYP isoenzyme for sub- CYP2D6ñ making up only 1-4% of the total CYP stances B and A (15, 19). The role of competitive monooxygenase pool in liver parenchyma but oxi- inhibitors can be played by concomitantly taken dizing as much as 22% of all oxidatively biotrans- drugs and their metabolites but also some food com- formed drugs; ponents, stimulants, environmental toxins and CYP2C9 ñ making up 13-21% of the total CYP metabolites of these xenobiotics. For example: monooxygenase pool in liver parenchyma and oxi- ñ caffeine is a competitive inhibitor of CYP1A1, dizing approximately 18% of all oxidatively bio- CYP1A2, CYP3A4 in reactions with drugs and their transformed drugs; metabolites concomitantly present in the organism, CYP2C19 ñ making up only 2-5% of the total CYP which are substrates for these isoenzymes (15, 20); monooxygenase pool in liver parenchyma and oxi- ñ ethanol is a competitive inhibitor of CYP2E1 in dizing approximately 9% of all oxidatively biotrans- reactions with drugs and their metabolites concomi- formed drugs. tantly present in the organism, which are substrates The following isoenzymes (in the order of per- for this isoenzyme (21); cent participation) also take part in drug biotransfor- ñ polycyclic aromatic hydrocarbons (PAH) of mation: CYP1A2, CYP2B6, CYP2E1, CYP2A6, tobacco smoke are competitive inhibitors of CYP2C8, CYP3A5, CYP3A7, CYP3A43, CYP1A1 CYP1A1, CYP1A2, CYP1B1 in reactions with (non-constitutive), CYP2C18, CYP3A3 (1, 6, 17). drugs and their metabolites concomitantly present in In addition to the above-mentioned CYP isoen- the organism, which are substrates for these isoen- zymes, when vitamins A and D or steroid hormones zymes (22). and their derivatives are used as drugs, the isoen- A known example for the system of competi- zymes typical for the metabolism of these com- tive inhibitors of many CYP isoenzymes is grape- pounds in their natural supply will participate in fruit juice, which contains (17, 23, 24): their biotransformation: ñ furanocoumarins: ñ CYP26A1, CYP26B1, CYP26C1 in the case of ● bergamottin, 6í,7;-dihydroxybergamottin and vitamin A and its derivatives (2, 13); bergapten ñ competitive inhibitors of CYP3A3, ñ CYP2R1, CYP11A1, CYP24A1, CYP27A1, CYP3A4, CYP3A5 and CYP2A6, CYP2A13, CYP27B1, CYP27C1 in the case of vitamin D and CYP2B6, CYP2C8, CYP2D6, CYP2E1, CYP2F1. its derivatives (6, 14); ● 5-geranyloxycoumarin, 7-geranyloxycoumarin, ñ ñ CYP11A1, CYP11B1, CYP11B2, CYP17A1, competitive inhibitors of CYP3A4, and CYP2A6, CYP19A1, CYP21A2 in the case of pharmacothera- CYP2D6; py with steroid hormones and their derivatives ● furanocoumarin dimers: GF-I-1, GF-I-4, GF-I-5, (among others: progesterone, testosterone, estradiol, GF-I-6 ñ competitive inhibitors of CYP3A4. estriol, 17β-estradiol, hydrocortisone) (6, 15). ñ flavonoids: Table 2 shows CYP isoenzymes responsible ● naringin and naringenin ñ competitive inhibitors for the metabolism of most drugs with their respec- of CYP3A4; tive endogenous and xenobiotic substrates and also ● kaempferol ñ a competitive inhibitor of CYP2E1 inducers and inhibitors. and CYP3A4; Drugs and their metabolites and other endoge- ● quercetin ñ a competitive inhibitor of CYP2C8. nous and xenobiotic compounds which are sub- Besides numerous competitive inhibitors, CYP strates of the same monooxygenase isoenzymes isoenzymes may be subject to the action of endoge- from the CYP superfamily, under conditions of nous and xenobiotic compounds acting as non-com- coexistence in the organism, compete for influence petitive inhibitors (Table 2). Permanent binding of in active center of the proper CYP isoenzyme. Thus the metabolites of some xenobiotic substances, they are competitive inhibitors of a given CYP including drugs, with the active center of the isoenzyme in relation to the biotransformation of enzyme is also possible ñ the so-called suicide inhi- another substrate of the same isoenzyme concomi- bition e.g. methoxalen in relation to CYP1A2, tantly present in the catalytic milieu. According to gestodene in relation to CYP3A4 (Table 2) (25). Cytochrome P450 polymorphism ñ molecular, metabolic and pharmacogenetic aspects. II... 317

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