Summary
Multiple hepatic P450 enzymes play an important role in the oxidative biotransformation of a vast number of structurally diverse drugs. As such, these enzymes are a major determinant of the pharmacokinetic behaviour of most therapeutic agents. There are several factors that influence P450 activity, either directly or at the level of enzyme regulation.
Drug elimination is decreased and the incidence of drug interactions is increased when there is competition between 2 or more drugs for oxidation by the same P450 enzyme. The available knowledge concerning the relationship between the presence of certain functional groups within the drug structure and inhibition of P450 activity is increasing. In many instances, it is possible to associate inhibition with certain drug classes, e.g. antimycotic imidazoles and macrolide antibiotics.
Disease states, especially those with hepatic involvement, and the genetic makeup of the individual are conditions in which some P450s may be downregulated (that is, the enzyme concentrations in liver are decreased), with associated slower rates of drug elimination. In these individuals, dosages of drugs that are substrates for downregulated P450s should be decreased.
Exposure to environmental pollutants as well as a large number of lipophilic drugs can result in induction (upregulation) of P450 enzyme activity. This raises the issue of previous approaches to the study of P450 induction in vivo. The use of human hepatocyte preparations in culture is a promising new direction that could assist the determination of modifications to drug therapy necessitated by exposure to inducing agents. Until such information is obtained, however, the use of drugs known to increase the microsomal expression of particular P450s, and increase associated drug oxidation capacity in humans, should be used with caution.
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References
Abernethy DR, Montamat SC. Acute and chronic studies of diltiazem in elderly versus young hypertensive patients. American Journal of Cardiology 60: 1161–1201, 1987
Alvan G, Grind M, Graffner C, Sjoqvist F. Relationship of N-demethylation of amiflamine and its metabolite to debrisoquine hydroxylation polymorphism. Clinical Pharmacology and Therapeutics 36: 515–519, 1984
Amouyal G, Larrey D, Letteron P, Geneve J, Labbe G, et al. Effects of methoxsalen on the metabolism of acetaminophen in humans. Biochemical Pharmacology 36: 2349–2352, 1987
Aoyama T, Gelboin HV, Gonzalez FJ. Mutagenic activation of 2-amino-3-methylimidazo[4,5f]quinoline by complementary DNA-expressed human liver P-450. Cancer Research 50: 2060–2063, 1990
Aoyama T, Yamano S, Waxman DJ, Lapenson DP, Meyer UA, et al. Cytochrome P-450 hPCN3, a novel cytochrome P-450 III A gene product that is differentially expressed in adult human liver: cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCNl and hPCN3 for the metabolism of steroid hormones and cyclosporine. Journal of Biological Chemistry 264: 10388–10395, 1989
Apseloff G, Shepard DR, Chembers MA, Nawoot S, Mays DC, et al. Inhibition and induction of theophylline metabolism by 8-methoxypsoralen: in vivo study in rats and humans. Drug Metabolism and Disposition 18: 298–303, 1990
Back DJ, Tjia J, Monig H, Ohnhaus EE, Park BK. Selective inhibition of drug oxidation after simultaneous administration of two probe drugs, antipyrine and tolbutamide. European Journal of Clinical Pharmacology 34: 157–163, 1988
Balant-Gorgia AE, Balant LP, Genet CH, Dayer P, Aeschlimann JM et al. Importance of oxidative polymorphism and levopromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites. European Journal of Clinical Pharmacology 31: 449–455, 1986
Balant-Gorgia AE, Schulz P, Dayer P, Balant L, Kubli A, et al. Role of oxidation polymorphism on blood and urine concentrations of amitriptyline and its metabolites in man. Archiv fur Psychiatrie und Nervenkrankheiten 232: 215–222, 1982
Bargetzi MJ, Aoyama T, Gonzalez FJ, Meyer UA. Lidocaine metabolism in human liver microsomes by cytochrome P450IIIA4. Clinical Pharmacology and Therapeutics 46: 521–527, 1989
Bartkowski RR, Goldberg ME, Larijani GE, Boerner T. Inhibition of alfentanil metabolism by erythromycin. Clinical Pharmacology and Therapeutics 46: 99–102, 1989
Beaune PH, Umbenhauer DR, Bork RW, Lloyd RS, Guengerich FP. Isolation and sequence determination of a cDNA clone related to human cytochrome P-450 nifedipine oxidase. Proceedings of the National Academy of Sciences of the USA 83: 8064–8068, 1986
Bertilsson L, Henthorn TK, Sanz E, Tybring G, Sawe J, et al. Importance of genetic factors in the regulation of diazepam metabolism. Relationship to S-mephenytoin, but not debrisoquine hydroxylation phenotype. Clinical Pharmacology and Therapeutics 45: 348–355, 1989
Bolt HM, Kappas H, Remmer H. Studies on the metabolism of ethynylestradiol in vitro and in vivo: the significance of 2-hydroxylation and the formation of polar products. Xenobiotica 3: 773–785, 1973
Bork RW, Muto T, Beaune PH, Srivastava PK, Lloyd RS, et al. Characterization of mRNA species related to human liver cytochrome P-450 nifedipine oxidase and the regulation of catalytic activity. Journal of Biological Chemistry 264: 910–919, 1989
Bourdi M, Larrey D, Nataf J, Bernuau J, Pessayre D, et al. Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P-450IA2: a specific marker of dihydralazine-induced hepatitis. Journal of Clinical Investigation 85: 1967–1973, 1990
BrØsen K, Skjelbo E. Fluoxetine and norfluoxetine are potent inhibitors of P450IID6 — the source of the sparteine/debrisoquine oxidation polymorphism. British Journal of Clinical Pharmacology 32: 136–137, 1991
BrØsen K, Zeugin T, Meyer UA. Role of P450IID6, the target of the sparteine-debrisoquine polymorphism, in the metabolism of imipramine. Clinical Pharmacology and Therapeutics 49: 609–617, 1991
Cantrill E, Murray M, Mehta I, Farrell GC. Downregulation of the male-specific hepatic microsomal steroid 16α-hydroxylase, cytochrome P-450 UT-A, in rats with portal bypass: relevance to estradiol accumulation and impaired drug metabolism in hepatic cirrhosis. Journal of Clinical Investigation 83: 1211–1216, 1989
Cooper RG, Evans DAP, Whibley EJ. Polymorphic hydroxylation of perhexiline maleate in man. Journal of Medical Genetics 21: 27–33, 1984
Dayer P, Balant L, Courvoisier F, Kupfer A, Kubli A, et al. The genetic control of bufuralol metabolism in man. European Journal of Drug Metabolism and Pharmacokinetics 7: 7377, 1982
Dayer D, Desmeules J, Leemann T, Striberni R. Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufl). Biochemical and Biophysical Research Communications 152: 411–416, 1988
Dayer P, Leemann T, Striberni R. Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytochrome P-450 db1 activity. Clinical Pharmacology and Therapeutics 45: 34–40, 1989
Devonshire HW, Kong I, Cooper M, Sloan TP, Idle JR, et al. The contribution of genetically determined oxidation status to inter-individual variation in phenacetin disposition. British Journal of Clinical Pharmacology 16: 157–166, 1983
Diaz D, Fabre I, Daujat M, Fabre G, Joyeux H, et al. The gastric antisecretory drug omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology 99: 737–747, 1990
Distelrath LM, Reilly PEB, Martin MV, Davis GG, Wilkinson GR, et al. Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. Journal of Biological Chemistry 260: 9057–9067, 1985
Donovan MA, Heagerty AM, Patel L, Castledon M, Pohl JEF. Cimetidine and the bioavailability of propranolol. Lancet 1: 164, 1981
Eichelbaum M, Bertilsson L, Sawe J, Zekorn C. Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities. Clinical Pharmacology and Therapeutics 31: 184–186, 1982
Ene MD, Roberts CJC. Pharmacokinetics of nifedipine after oral administration in chronic liver disease. Journal of Clinical Pharmacology 27: 1001–1004, 1987
Fonne-Pfister R, Meyer UA. Xenobiotic and endobiotic inhibitors of cytochrome P-450dbl function, the target of the debrisoquine/sparteine type polymorphism. Biochemical Pharmacology 37: 3829–3835, 1988
Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer UA. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. American Journal of Human Genetics 48: 943–950, 1991
Ged C, Umbenhauer DR, Bellew TM, Bork RW, Srivastava PK, et al. Characterization of cDNAs, mRNAs, and proteins related to human liver microsomal cytochrome P-450 (S)mephenytoin 4′-hydroxylase. Biochemistry 27: 6929–6940, 1988
Gerber MC, Tejwani GA, Gerber N, Bianchine JR. Drug interactions with cimetidine. An update. Pharmacology and Therapeutics 27: 353–370, 1985
Gonzalez FJ, Schmid BJ, Umeno M, McBride OW, Hardwick JP, et al. Human p450PCNl. Sequence, chromosomal localization, and direct evidence through cDNA expression that p450PCNl is nifedipine oxidase. DNA 7: 79–86, 1988a
Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, et al. Characterization of the common defect in humans deficient in debrisoquine metabolism. Nature 331: 442–446, 1988b
Gonzalez FJ, Vilbois F, Hardwick JP, McBride OW, Nebert DW, et al. Human debrisoquine 4-hydroxylase (P450IID1). cDNA and deduced amino acid sequence and mapping of the CYP2D locus to chromosome 22. Genomics 2: 174–179, 1988c
Gueguen M, Boniface O, Bernard O, Clerc F, Cartwright T, et al. Identification of the main epitope on human cytochrome P450 IID6 recognised by anti-liver kidney microsome antibody. Journal of Autoimmunity 4: 607–615, 1991
Guengerich FP. Oxidation of 17α-ethynylestradiol by human liver cytochrome P-450. Molecular Pharmacology 33: 500–508, 1988
Guengerich FP. Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. Chemical Research in Toxicology 3: 363–371, 1990
Guengerich FP, Turvy CG. Comparison of levels of several human microsomal cytochrome P-450 enzymes and epoxide hydrolase in normal and disease states using immunochemical analysis of surgical liver samples. Journal of Pharmacology and Experimental Therapeutics 256: 1189–1191, 1991
Gurtoo HL, Marinello AJ, Struck RF, Paul B, Dahms RP. Studies on the mechanism of denaturation of cytochrome P-450 by cyclophosphamide and its metabolites. Journal of Biological Chemistry 256: 11691–11701, 1981
Haefeli WE, Bargetzi MJ, Follath F, Meyer UA. Potent inhibition of cytochrome P450IID6 (debrisoquine 4-hydroxylase) by flecainide in vitro and in vivo. Journal of Cardiovascular Pharmacology 15: 776–779, 1990
Hall SD, Guengerich FP, Branch RA, Wilkinson GR. Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes. Journal of Pharmacology and Experimental Therapeutics 240: 216–222, 1987
Halpert J, Balfour C, Miller NE, Morgan ET, Dunbar D, et al. Isozyme selectivity of the inhibition of rat liver cytochromes P-450 by chloramphenicol in vivo. Molecular Pharmacology 28: 290–296, 1985
Hassell D, Utt JK. Suspected interaction. Warfarin and erythromycin. Southern Medical Journal 78: 1015–1016, 1985
Helsby NA, Ward SA, Howells RE, Breckenridge AM. In vitro metabolism of the biguanide antimalarials in human liver microsomes: evidence for a role of the mephenytoin hydroxylase (P450 MP) enzyme. British Journal of Clinical Pharmacology 30: 287–291, 1990
Hetzel DJ, Bochner F, Hallpike JF, Shearman DJC, Hann CS. Cimetidine interaction with phenytoin. British Medical Journal 282: 1512, 1981
Homberg JC, Abuaf N, Helmy-Khalil S, Biour M, Poupon R, et al. Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies. Hepatology 5: 722–727, 1985
Ikeya K, Jaiswal AK, Owens RA, Jones JE, Nebert DW, et al. Human CYP1A2. Sequence, gene structure, comparison with the mouse and rat orthologous gene, and genetic differences in liver 1A2 mRNA concentrations. Molecular Endocrinology 3: 1399–1408, 1989
Inaba T, Jurima M, Mahon WA, Kalow W. In vitro inhibition studies of two isozymes of human liver cytochrome P-450: mephenytoin p-hydroxylase and sparteine monooxygenase. Drug Metabolism and Disposition 13: 443–448, 1985
Janknegt R. Drug interactions with quinolones. Journal of Antimicrobial Chemotherapy 26 (Suppl. D): 7–29, 1990
Jung-Hoffman C, Kuhl H. Interaction with the pharmacokinetics of ethinylestradiol and progestogens contained in oral contraceptives. Contraception 40: 299–312, 1989
Kalow W. The genetic defect of mephenytoin hydroxylation. Xenobiotica 16: 379–389, 1986
Kalow W. Genetic variation in the human hepatic cytochrome P-450 system. European Journal of Clinical Pharmacology 31: 633–641, 1987
Kimura S, Pastewka J, Gelboin HV, Gonzalez FJ. cDNA and amino acid sequences of two members of the human P450IIC gene subfamily. Nucleic Acids Research 15: 10053–10054, 1987
Kitchen I, Tremblay J, Andre J, Dring LG, Idle JR, et al. Inter-individual and interspecies variation in the metabolism of the hallucinogen 4-methoxyamphetamine. Xenobiotica 9: 397–404, 1979
Kleinbloesem CH, van Brummelen P, Faber H, Danhof M, Vermeulen NPE, et al. Variability in nifedipine pharmacokinetics and dynamics: a new oxidation polymorphism in man. Biochemical Pharmacology 33: 3721–3724, 1984
Klotz U, Reimann I. Delayed clearance of diazepam due to cimetidine. New England Journal of Medicine 302: 1012–1014, 1980
Knodell RG, Hall SD, Wilkinson GR, Guengerich FP. Hepatic metabolism of tolbutamide. Characterization of the form of cytochrome P-450 involved in methyl hydroxylation and relationship to in vivo disposition. Journal of Pharmacology and Experimental Therapeutics 241: 1112–1119, 1987
Knodell RG, Dubey RK, Wilkinson GR, Guengerich FP. Oxidative metabolism of hexobarbital in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation. Journal of Pharmacology and Experimental Therapeutics 245: 845–849, 1988
Kolyada AY. Sequence of a human liver cytochrome P-450 cDNA clone. Nucleic Acids Research 18: 5550, 1990
Komori M, Nishio K, Fujitani T, Ohi H, Kitada M, et al. Isolation of a new human fetal liver cytochrome P450 cDNA clone: evidence for expression of a limited number of forms of cytochrome P450 in human fetal livers. Archives of Biochemistry and Biophysics 272: 219–225, 1989a
Komori M, Nishio K, Ohi H, Kitada M, Kamataki T. Molecular cloning and sequence analysis of cDNA containing the entire coding region for human fetal liver cytochrome P-450. Journal of Biochemistry 105: 161–163, 1989b
Kroemer HK, Mikus G, Kronbach T, Meyer UA, Eichelbaum M. In vitro characterization of the human cytochrome P-450 involved in the polymorphic oxidation of propafenone. Clinical Pharmacology and Therapeutics 45: 28–33, 1989
Kronbach T, Mathys D, Umeno M, Gonzalez FJ, Meyer UA. Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Molecular Pharmacology 36: 89–96, 1989
Labout JJM, Thijssen CT, Keijser GGJ, Hespe W. Differences between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man. European Journal of Clinical Pharmacology 21: 343–350, 1982
Lennard MS, Tucker GT, Silas JH, Woods HF. Debrisoquine polymorphism and the metabolism and action of metoprolol, timolol, propranolol and atenolol. Xenobiotica 16: 435–447, 1986
Liddle C, Murray M, Farrell GC. Effect of liver regeneration on hepatic cytochrome P450 isozymes and serum sex steroids in the male rat. Gastroenterology 96: 864–872, 1989
Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. Journal of Clinical Investigation 71: 1495–1499, 1983
Lunetta JM, Sugiyama K, Correia MA. Secobarbital-mediated inactivation of rat liver cytochrome P-450b: a mechanistic reappraisal. Molecular Pharmacology 35: 10–17, 1989
Mays DC, Camisa C, Cheney P, Pacula CM, Nawoot S, et al. Methoxsalen is a potent inhibitor of the metabolism of caffeine in humans. Clinical Pharmacology and Therapeutics 39: 265–270, 1987
McGourty JC, Silas JH, Lennard MS, Tucker GT, Woods HF. Metoprolol metabolism and debrisoquine oxidation polymorphism — population and family studies. British Journal of Clinical Pharmacology 20: 555–566, 1985
Mellstrom B, Bertilsson L, Sawe J, Schulz HU, Sjoqvist F. E- and Z-10-Hydroxylation of nortriptyline. Relationship to polymorphic debrisoquine hydroxylation. Clinical Pharmacology and Therapeutics 30: 189–193, 1981
Miles JS, McLaren AW, Forrester LM, Glancey MJ, Lang MA, et al. Identification of the human liver cytochrome P-450 responsible for coumarin 7-hydroxylase activity. Biochemical Journal 267: 365–371, 1990
Miles JS, Spurr NK, Gough AC, Jowett T, McLaren AW, et al. A novel human cytochrome P450 gene (P450IIB): chromosomal localization and evidence for alternate splicing. Nucleic Acids Research 16: 5783–5795, 1988
Molowa DT, Scheutz EG, Wrighton SA, Watkins PB, Kremers P, et al. Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proceedings of the National Academy of Sciences of the USA 83: 5311–5315, 1986
Montamat SC, Abernethy DR. N-Monodemethyldiltiazem is the predominant metabolite of diltiazem. British Journal of Clinical Pharmacology 24: 185–189, 1987
Mortimer O, Persson K, Ladona MG, Spalding D, Zanger UM, et al. Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: relation to the presence of immunoidentified cytochrome P-450IID1. Clinical Pharmacology and Therapeutics 47: 27–35, 1990
Murray M, Reidy GF. Selectivity in the inhibition of mammalian cytochromes P-450 by chemical agents. Pharmacological Reviews 42: 85–101, 1990
Murray M, Zaluzny L, Dannan GA, Guengerich FP, Farrell GC. Altered regulation of cytochrome P-450 enzymes in cholinedeficient cirrhotic male rat liver: impaired regulation and activity of the male-specific androst-4-ene-3,17-dione 16α-hydroxylase, cytochrome P-450UT-A, in hepatic cirrhosis. Molecular Pharmacology 31: 117–121, 1987a
Murray M, Zaluzny L, Farrell GC. Impaired androgen 16α-hydroxylation in hepatic microsomes from carbon tetrachloride-cirrhotic male rats. Gastroenterology 93: 141–147, 1987b
Murray M, Zaluzny L. Comparative effects of antithrombotic and antimycotic N-substituted imidazoles on rat hepatic microsomal steroid and xenobiotic hydroxylases in vitro. Biochemical Pharmacology 37: 415–420, 1988
Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz E, et al. Interethnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Clinical Pharmacology and Therapeutics 38: 402–408, 1985
Nebert DW, Nelson DR, Coon MJ, Estabrook RW, Feyereisen R, et al. The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA and Cell Biology 10: 1–14, 1991
Oates NS, Shah RR, Idle JR, Smith RL. Genetic polymorphism of phenformin 4-hydroxylation. Clinical Pharmacology and Therapeutics 32: 81–89, 1982
Okino ST, Quattrochi LC, Pendurthi UR, McBride OW, Tukey RH. Characterization of multiple human cytochrome P4501 cDNAs. Journal of Biological Chemistry 262: 16072–16079, 1987
Pichard L, Gillet G, Fabre I, Dalet-Beluche I, Bonfils C, et al. Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem. Drug Metabolism and Disposition 18: 711–719, 1990
Pierce DM, Smith SE, Franklin RA. The pharmacokinetics of indoramin and 6-hydroxyindoramin in poor and extensive hydroxylators of debrisoquine. European Journal of Clinical Pharmacology 33: 59–65, 1987
Quattrochi LC, Tukey RH. The human cytochrome CYP1A2 gene contains regulatory elements responsive to 3-methylcholanthrene. Molecular Pharmacology 36: 61–71, 1989
Raucy JL, Lasker JM, Lieber CS, Black M. Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2. Archives of Biochemistry and Biophysics 271: 270–283, 1989
Reidy GF, Mehta I, Murray M. Inhibition of oxidative drug metabolism by orphenadrine: in vitro and in vivo evidence for isozyme-specific complexation of cytochrome P-450 and inhibition kinetics. Molecular Pharmacology 35: 736–743, 1989
Relling MV, Evans WE, Fonne-Pfister R, Meyer UA. Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquine and mephenytoin hydroxylase, in human liver microsomes. Cancer Research 49: 68–71, 1989
Relling MV, Aoyama T, Gonzalez FJ, Meyer UA. Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily. Journal of Pharmacology and Experimental Therapeutics 252: 442–447, 1990
Romkes M, Raucy JL, Goldstein JA. Characterization and amino acid structure of cDNAs from two members of the human P450IIC gene subfamily. Abstract no. 3181. FASEB Journal 4: A2244, 1990
Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA. Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. Biochemistry 30: 3247–3255, 1991
Roy SD, Hawes EM, Hubbard JW, McKay G, Midha KK. Methoxyphenamine and dextromethorphan as safe probes for debrisoquine hydroxylation polymorphism. Lancet 2: 1393, 1984
Sarkar M, Polk RE, Guzelian PS, Hunt C, Karnes HT. In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes. Antimicrobial Agents and Chemotherapy 34: 594–599, 1990
Schuetz EG, Li D, Omiecinski CJ, Muller-Eberhard U, Kleinman HK, et al. Regulation of gene expression in adult rat hepatocytes cultured on a basement membrane matrix. Journal of Cellular Physiology 134: 309–323, 1988
Schuetz JD, Molowa DT, Guzelian PS. Characterization of a cDNA encoding a new member of the glucocorticoid-responsive cytochromes P450 in human liver. Archives of Biochemistry and Biophysics 274: 355–365, 1989
Shah RR, Oates NS, Idle JR, Smith RL. Beta-blockers and drug oxidation status. Lancet 1: 508–509, 1982
Shephard EA, Phillips IR, Santisteban I, Palmer CNA, Povey S. Cloning, expression, and chromosomal localization of a member of the human cytochrome P450IIC gene subfamily. Annals of Human Genetics 53: 23–31, 1989
Shimada T, Misono KS, Guengerich FP. Human liver microsomal cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism: purification and characterization of two similar forms involved in the reaction. Journal of Biological Chemistry 261: 909–921, 1986
Silver BA, Bell WR. Cimetidine potentiates the hypoprothrombinemic effect of warfarin. Annals of Internal Medicine 90: 348–349, 1979
Sloan TP, Mahgoub A, Lancaster R, Idle JR, Smith RL. Polymorphism of carbon oxidation of drugs and clinical implications. British Medical Journal 2: 655–657, 1978
Sloan TP, Sale JR, Smith RL. Influence of DH/DL alleles regulating debrisoquine oxidation on phenytoin hydroxylation. Clinical Pharmacology and Therapeutics 29: 493–497, 1981
Smith RL. Human genetic variations in oxidative drug metabolism. Xenobiotica 16: 361–365, 1986
Song BJ, Gelboin HV, Park SS, Yang CS, Gonzalez FJ. Complementary DNA and protein sequences of ethanol-inducible rat and human cytochrome P-450s. Journal of Biological Chemistry 261: 16689–16697, 1986
Spina E, Birgersson C, von Bahr C, Ericsson O, Mellstrom B, et al. Phenotypic consistency in hydroxylation of demethylimipramine and debrisoquine in healthy subjects and in human liver microsomes. Clinical Pharmacology and Therapeutics 36: 677–682, 1984
Srivastava P, Yun C-H, Beaune PH, Ged C, Guengerich FP. Separation of human liver microsomal tolbutamide hydroxylase and (S)-mephenytoin 4′-hydroxylase cytochrome P-450 enzymes. Molecular Pharmacology 40: 69–79, 1991
Tinel M, Belghiti J, Descatoire V, Amouyal G, Letteron P, et al. Inactivation of human liver cytochrome P-450 by the drug methoxsalen and other psoralen derivatives. Biochemical Pharmacology 36: 951–955, 1987
Tsao SC, Dickinson TH, Abernethy DR. Metabolite inhibition of parent drug biotransformation: studies of diltiazem. Drug Metabolism and Disposition 18: 180–182, 1990
Tyndale RF, Kalow W, Inaba T. Oxidation of reduced haloperidol to haloperidol. Involvement of human P450IID6 (sparteine/debrisoquine monooxygenase). British Journal of Clinical Pharmacology 31: 655–660, 1991
Umbenhauer DR, Martin MV, Lloyd RS, Guengerich FP. Cloning and sequence determination of a complementary DNA related to human liver microsomal cytochrome P-450 S-mephenytoin 4-hydroxylase. Biochemistry 26: 1094–1099, 1987
Veronese ME, Mackenzie PI, Doecke CJ, McManus ME, Miners JO, et al. Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9. Biochemical and Biophysical Research Communications 175: 1112–1118, 1991
von Bahr C, Movin G, Nordin C, Liden A, Hammarlund-Udenaes M et al. Plasma levels of thioridazine and metabolites are influenced by the debrisoquine hydroxylation phenotype. Clinical Pharmacology and Therapeutics 49: 234–240, 1991
Wang T, Roden DM, Wolfenden HT, Woosley RL, Wood AJJ, et al. Influence of genetic polymorphism on the metabolism and disposition of encainide in man. Journal of Pharmacology and Experimental Therapeutics 228: 605–611, 1984
Ward SA, Walle T, Walle UK, Wilkinson GR, Branch RA. Propranolol’s metabolism is determined by both mephenytoin and debrisoquine hydroxylase activities. Clinical Pharmacology and Therapeutics 45: 72–79, 1989
Watkins PB, Murray SA, Winkelman LG, Heumann DM, Wrighton SA, et al. Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450: studies in rats and patients. Journal of Clinical Investigation 83: 688–697, 1989
Wedlund PJ, Aslanian WS, Jacqz E, McAllister CB, Branch RA, et al. Phenotypic differences in mephenytoin pharmacokinetics in normal subjects. Journal of Pharmacology and Experimental Therapeutics 234: 662–669, 1985
Weinberger M, Hudgel D, Spector S, Chidsey C. Inhibition of theophylline clearance by troleandomycin. Journal of Allergy and Clinical Immunology 59: 228–231, 1977
Wilkinson CF, Hetnarski K, Yellin TO. Imidazole derivatives — a new class of microsomal enzyme inhibitors. Biochemical Pharmacology 21: 3187–3192, 1972
Wilkinson GR, Schenker S. Drug disposition and liver disease. Drug Metabolism Reviews 4: 139–175, 1975
Wrighton SA, Brian WR, Sari MA, Iwasaki M, Guengerich FP, et al. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Molecular Pharmacology 38: 207–213, 1990
Yamano S, Nagata K, Yamazoe Y, Kato R, Gelboin HV, et al. cDNA and deduced amino acid sequences of human P450 IIA3. Nucleic Acids Research 17: 4888, 1989a
Yamano S, Nhamburo PT, Aoyama T, Meyer UA, Inaba T, et al. cDNA cloning and sequence and cDNA-directed expression of human P450 IIB1: identification of a normal and two variant cDNAs derived from the CYP 2B locus on chromosome 19 and differential expression of the IIB mRNAs in human liver. Biochemistry 28: 7340–7348, 1989b
Yamano S, Tatsuno J, Gonzalez FJ. The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes. Biochemistry 29: 1322–1329, 1990
Zanger UM, Hauri HP, Loeper J, Homberg JC, Meyer UA. Antibodies against human cytochrome P-450dbl in autoimmune hepatitis type II. Proceedings of the National Academy of Sciences of the USA 85: 8256–8260, 1988
Zekorn C, Achtert G, Hausleiter HJ, Moon CH, Eichelbaum M. Pharmacokinetics of N-propylajmaline in relation to polymorphic sparteine oxidation. Klinische Wochenschrift 63: 1180–1186, 1985
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Murray, M. P450 Enzymes. Clin-Pharmacokinet 23, 132–146 (1992). https://doi.org/10.2165/00003088-199223020-00005
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DOI: https://doi.org/10.2165/00003088-199223020-00005