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Human Cytochrome P450 3A4: Enzymatic Properties of a Purified

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Human Cytochrome P450 3A4: Enzymatic Properties of a Purified Proc. Natl. Acad. Sci. USA Vol. 90, pp. 11748-11752, December 1993 Pharmacology Human cytochrome P450 3A4: Enzymatic properties of a purified recombinant fusion protein containing NADPH-P450 reductase (drug metabolism/erythromycin/steroid 63-hydroxylation) MANJUNATH S. SHET, CHARLES W. FISHER, PRISCILLA L. HOLMANS, AND RONALD W. ESTABROOK Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9038 Contributed by Ronald W. Estabrook, September 9, 1993 ABSTRACT Human cytochrome P450 3A4is recognized as Recombinant CYP3A4 has been expressed in Escherichia the catalyst for the oxygen-dependent metaboism of a diverse coli (12, 13), yeast (14), and various cell lines (15) and shown group of medicafly important chemicals, inWuding the immu- to function in the metabolism of aflatoxin B1, testosterone, nosuppressive agent cyclosporin; macrolide antibiotics, such as nifedipine, and lidocaine, to name but a few of the substrates erythromycin; drugs such as benzphetamine, nifedipine, and tested. P450 3A4 expressed in human lymphoblastoid cells cocaine; and steroids, such as cortisol and testosterone to name has been used to evaluate cytotoxic and mutagenic responses but a few. We have engineered the cDNA for human cytochrome to various chemicals (15). P450 3A4 by linkage to the cDNA for the rat or human We describe here results of experiments designed to eval- flavoprotein, NADPH-P450 reductase (NADPH:ferrihemopro- uate the enzymatic properties of a purified recombinant tein oxidoreductase, EC 1.6.2.4). An enzymaticafly active fusion fusion protein containing the heme domain of human protein (rF450[mHum3A4/mRatOR]Ll) has been expressed at CYP3A4 and the flavoprotein domain of rat NADPH-P450 high levels in Escherichia coli and purified to homogeneity. reductase (NADPH:ferrihemoprotein oxidoreductase, EC Enzymatic studies show a requirement for lipid, detergent, and 1.6.2.4). This fusion protein is active in the metabolism of cytochrome bs for the 63-hydroxylation of steroids and the many steroids and drugs in a reaction dependent on the N-oxidation of nifedipine. In contrast, these additions are not presence of lipid, detergent, and cytochrome b5. The N-de- required for the N-demethylation oferythromycin or benzphet- methylation of the antibiotic erythromycin, as well as drugs amine. A spectrophotometricafly detectable metabolite complex such as benzphetamine and imipramine, does not require of P450 3A4 is formed during the metabolism of triacetylolean- these additives. In vitro studies designed to measure inhibi- domycin, and this has a pronounced inhibitory effect on the tion by a number of compounds reported as substrates for These re- CYP3A4 were carried out to determine their influence on the metabolim of both testosterone and erthromycin. 63-hydroxylation of testosterone or the N-demethylation of suits relate to the interpretation of current methods used to erythromycin. These studies revealed a number of unex- assess the in vivo activity of P450 3A4. plained differences in this in vitro measure of potential drug-drug interactions. Formation of a metabolite-inhibitor One ofthe most versatile ofthe cytochrome P450s is the form complex during the metabolism of low levels of TAO is present in human liver called CYP3A4, which catalyzes the inhibitory to the metabolism of both testosterone and eryth- oxidative metabolism of a wide array of different chemicals romycin. These results demonstrate the usefulness of this with markedly different structural characteristics (1). Interest recombinant fusion enzyme in evaluating the profiles of drug has centered on this P450 since it is reported to be one of the and steroid metabolism by this versatile human cytochrome more abundant P450s in human liver (2); it is inducible by a P450. Furthermore, these studies relate to the interpretation variety of agents including glucocorticoids as well as pheno- of the erythromycin breath test as an indicator of the in vivo barbital (3); it appears to play a central role in the metabolism function of CYP3A4 in the metabolism of other drugs. of the immunosuppressive cyclic peptide cyclosporin A as well as macrolide antibiotics, such as erythromycin (4); it also catalyzes the 63-hydroxylation of a number of steroids in- MATERIALS AND METHODS cluding testosterone, progesterone, and cortisol (5). Clinical Construction of Plasmids. The plasmid pCWori+: :bovl7A- interest relates to the measurement of erythromycin metab- rORfus described for the expression of the fusion protein olism by a breath test (6) and the presence of6f-hydroxylated rF450[mBovl7A/mRatOR]L1 (r, recombinant; F, fused; steroids in urine (7) as indicators of CYP3A4 function for 450, P450; m, modified cDNA; Bov or Rat, species; 17A, evaluation of transplant recipients. family name of P450; OR, NADPH-P450 reductase; Li, P450s ofthe 3A family were first characterized by Guzelian linker type), containing the cDNA of P450 17A linked to the and colleagues (8) based on the ability ofthe catabolic steroid cDNA of rat NADPH-P450 reductase, was modified in a pregnenolone-16a-carbonitrile to induce a unique form of manner similar to that described for the construction of the P450 (which they called P-450p). They also recognized the plasmid used for expression of the fusion protein containing ability of the macrolide antibiotic triacetyloleandomycin a rat liver w-hydroxylase, rF450[mRat4Al/mRatOR]L1 (16). (TAO) to serve as a powerful inducer ofthis type of P450-a A Agtll clone (NF-25) containing the nucleotide sequence for result of interest because of the known ability of TAO and the open reading frame ofhuman P450 3A4 was obtained from other compounds to form stable, metabolite-inhibitor com- F. P. Guengerich (Vanderbilt University, Nashville, TN) and plexes with P450 (9). Reconstitution studies using purified used for PCR mutagenesis with the oligonucleotide GT- P450s of the 3A family have shown the need to include CATATGGCTCTGTTATTAGCAGTTTTTCTGGTGC- phospholipids, detergents, and cytochrome b5 when testing TCCTC as the 5' primer and CCTCTAGACTAGTCAGGC- enzymatic activities (10, 11). TCCACTTACGGTGCC as the 3' primer. A portion of the coding sequence for the N terminus of P450 3A4 was deleted The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviations: TAO, triacetyloleandomycin; CHAPS, 3-[(3- in accordance with 18 U.S.C. §1734 solely to indicate this fact. cholamidopropyl)dimethylammoniol-l-propanesulfonate. 11748 Downloaded by guest on September 30, 2021 Pharmacology: Shet et al. Proc. Natl. Acad. Sci. USA 90 (1993) 11749 and replaced with a 27-bp fragment of the bovine 17A RESULTS modified by Barnes et al. (17) as described by Fisher et al. (12). The C terminus of P450 3A4 was modified by incorpo- Effect of Lipid, Detergent, and Cytochrome b5 on the rating a Sal I site encoding Ser-Thr as a dipeptide linker Metabolism of Nifedipine and the 6(-Hydroxylation of Testos- replacing the TGA stop codon to allow fusion with the terone. The in vitro metabolism of many chemicals by P450s modified DNA sequence of NADPH-P450 reductase as de- ofthe 3A family require the addition of a number ofadditives scribed (16). The plasmid encoding rF450[mBovl7A/ mixed together in an appropriate sequence. Incubation ofthe mRatOR]Ll was digested with Nde I and Sal I to remove the diluted purified fusion protein, rF450[mHum3A4/mRa- P450 17A domain and this digested plasmid, containing only tOR]L1, in the same manner as used with other P450- the rat reductase domain, was ligated with the Nde I/Sal I containing fusion proteins (16), resulted in little or no me- PCR amplified human P450 3A4 domain. Restriction digests tabolism of testosterone or nifedipine (Fig. 1 A and B). As confirmed that the 3A4 segment was incorporated in the described by Imaoka et al. (10) and Eberhart and Parkinson correct orientation. This plasmid is called (11), preincubation of the undiluted purified enzyme with pCWori+::hum3A4-rORfus. Recombinant human and rat cy- purified cytochrome b5, detergent, and phospholipid (in this tochrome b5, containing a histidine domain, were purified sequence), followed by dilution in the buffer mixture, results from E. coli membranes in which the cDNAs were expressed in optimal enzymatic activities. A systematic study of the by using a T7 expression system (ref. 18; unpublished re- requirement for phospholipid indicates a greater effective- sults). ness with those phospholipids containing unsaturated fatty Cell Growth, Disruption, and Purification of the Enzyme. E. acids-e.g., dioleoylphosphatidylserine (11). Most effective coli DH5a was transformed, plated, selected, and grown at was a sonicated suspension of a lipid extract prepared from 26°C as described (16) (with the omission of the rare salts rat liver microsomes (14). We find that a small amount of mixture in the growth medium). Cells were generally har- detergent (0.05% CHAPS) also must be included in the vested after 72 hr of growth and expressed 150-200 nmol of reaction mixture. This requirement for phospholipid and spectrophotometrically detectable P450 per liter of growth detergent is in sharp contrast to our results obtained when medium. It was noted that the expression of this fusion studying the enzymatic properties of other P450-containing protein is very sensitive to variation in growth conditions. fusion proteins (e.g., rF450[mBovl7A/mRatOR]L1 or Cells were disrupted by sonic treatment
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