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Cytochrome P450 Enzymes and Drug Metabolism—Basic Concepts and Methods of Assessment

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Abstract

1. The cytochrome P450 enzyme family is one of the major drug metabolizing systems in man.

2. Factors such as age, gender, race, environment, and drug treatment may have considerable influence on the activity of these enzymes.

3. There are now well-established in vitro techniques for assessing the role of specific cytochrome P450 enzymes in the metabolism of drugs, as well as the inhibitory or inducing effects of drugs on enzyme activity. In vitro data have been utilized to predict clinical outcomes (i.e., pharmacokinetic interactions), with close correlations between in vitro and in vivo data.

4. This information can be of considerable practical assistance to clinicians, to help with rational prescribing or to prevent or minimize the potential for drug interactions.

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REFERENCES

  • Agundez, J. A. G., Ledesma, M. C., Ladero, J. M., and Benitez, J. (1995). Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin. Pharmacol. Ther. 57:265–269.

    Google Scholar 

  • Ahsan, C. H., Renwick, A. G., Waller, D. G., Challenor, V. F., George, C. F., and Amanulah, M. (1993). The influences of dose and ethnic origins on the pharmacokinetics of nifedipine. Clin. Pharmacol. Ther. 54:329–338.

    Google Scholar 

  • Bailey, D. G., Arnold, J. M. O., and Spence, J. D. (1994). Grapefruit juice and drugs. Clin. Pharmacokinet. 26:91–98.

    Google Scholar 

  • Balant-Gorgia, A. E., Balant, L. P., and Garrone, G. (1989). High blood concentrations of imipramine or clomipramine and therapeutic failure: a case report study using drug monitoring data. Ther. Drug Monit. 11:415–420.

    Google Scholar 

  • Barry, M., and Feely, J. (1990). Enzyme induction and inhibition. Pharmacol. Ther. 48:71–94.

    Google Scholar 

  • Benitez, J., Carrillo, J. A., and Herraiz, A. G. (1994). Higher incidence of side effects in psychiatric patients poor metabolizers of debrisoquine. Clin. Pharmacol. Ther. 55:170.

    Google Scholar 

  • Bertilsson, L., Aberg-Wistedt, A., Gustafsson, L. L., and Nordin, C. (1985). Extremely rapid hydroxylation of debrisoquine: A case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther. Drug. Monit. 7:478–480.

    Google Scholar 

  • Bertilsson, L., Mellstrom, B., Sjoqvist, F., et al., (1981). Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: Clinical implications. Lancet 1:560–561.

    Google Scholar 

  • Bertilsson, L., Lou, L.-Q., Du, Y.-L., Liu, Y., Kuang, T.-Y., Liao, X.-M., Wang, K.-Y., Reviriego, J., Iselius, L., and Sjoqvist, F. (1992). Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquine and S-mephenytoin. Clin. Pharmacol. Ther., 51:388–397.

    Google Scholar 

  • Bertilsson, L., Dahl, M.-L., Sjoqvist, F., Aberg-Wistedt, A., Humble, M., Johansson, I., Lundqvist, E., and Ingelman-Sundberg, M. (1993). Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 341:63.

    Google Scholar 

  • Black, D. J., Kunze, K. L., Wienkers, L. C., Gidal, B. E., Seaton, T. L., McDonnell, N. D., Evans, J. S., Bauwens, J. E., and Trager, W. F. (1996). Warfarin-fluconazole II: A metabolically based drug interaction: in vivo studies. Drug Metab. Disp. 34:422–428.

    Google Scholar 

  • Chen, S., King, V., Wedlund, P. J., and Hays, L. (1995). Cytochrome P450–2D6 (CYP2D6): Simplified screening for the A and B alleles and deficient enzyme expression. Clin. Pharmacol. Ther., 57:150.

    Google Scholar 

  • Chen, S., Chou, W.-H., Blouin, R. A., Mao, Z., Humphries, L. L., Meek, C., Neill, J. R., Martin, W. L., Hays, L. R., and Wedlund, P. J. (1996). The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: Screening costs and influence on clinical outcomes in psychiatry. Clin. Pharmacol. Ther. 60:522–534.

    Google Scholar 

  • Dahl, M.-L., Johannson, I., Palmertz, M. P., Ingelman-Sundberg, M., and Sjoqvist, F. (1992). Analysis of the CYP2D6 gene in relation to debrisoquine and desipramine hydroxylation in a Swedish population. Clin. Pharmacol. Ther. 51:12–17.

    Google Scholar 

  • de Morais, S. M. F., Wilkinson, G. R., Blaisdell, J., Nakamura, K., Meyer, U. A., and Goldstein, J. A. (1994a). The major genetic defect responsible for the polymorphism of S-mephenytoin in human. J. Biol. Chem. 269:15419–15422.

    Google Scholar 

  • de Morais, S. M. F., Wilkinson, G. R., Blaisdell, J., Meyer, U. A., Nakamura, K., and Goldstein, J. A. (1994b). Identification of a new genetic defect responsible for the polymorphism of S-mephenytoin metabolism in Japanese. Mol. Pharmacol. 46:594–598.

    Google Scholar 

  • Doshi, B. S., Kulkarni, R. D., Chauhan, B. L., and Wilkinson, G. L. (1990). Frequency of impaired-mephenytoin hydroxylation in an Indian population. Br. J. Clin. Pharmacol. 30:779–780.

    Google Scholar 

  • Eichelbaum, M. (1982). Defective oxidation of drugs: pharmacokinetic and therapeutic implications. Clin. Pharmacokinet. 7:1–22.

    Google Scholar 

  • Engel, G., Hofmann, U., Heidemann, H., Cosme, J., and Eichelbaum, M. (1996). Antipyrine as a probe for human oxidative metabolism: identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxmethylantipyrine, and norantipyrine formation. Clin. Pharmacol. Ther. 59:613–623.

    Google Scholar 

  • Estabrook, R. W., (1996). The remarkable P450s: A historical overview of these versatile hemoprotein catalysts. FASEB J. 10:202–204.

    Google Scholar 

  • Ford, J. M., Truman, C. A., Wilcock, G. K., and Roberts, C. J. (1993). Serum concentrations of tacrine hydrochloride predict its adverse effects in Alzheimer's disease. Clin. Pharmacol. Ther. 53:691–695.

    Google Scholar 

  • Garfinkel, D. (1958). Studies on pig liver microsomes. 1. Enzymic and pigment composition of different microsomal fractions. Arch. Biochem. Biophys. 77:493–509.

    Google Scholar 

  • Glue, P., and Banfield, C. R. (1996). Psychiatry, psychopharmacology and P450s. Human Psychopharmacol. 11:97–114.

    Google Scholar 

  • Goff, D. C., Henderson, D. C., and Amico, E. (1992). Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am. J. Psychiat. 149:1189–1194.

    Google Scholar 

  • Gonzales, F. J., and Korzekwa, K. R. (1995). Cytochromes P450 expression systems. Annu. Rev. Pharmacol. Toxicol. 35:369–390.

    Google Scholar 

  • Hammer, W., and Sjoqvist, F. (1967). Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. Life Sci. 6:1895–1903.

    Google Scholar 

  • Harris, R. Z., Benet, L. Z., and Schwartz, J. B. (1995). Gender effects in pharmacokinetics and pharmacodynamics. Drugs 50: 222–239.

    Google Scholar 

  • Harvey, A. T., and Preskorn, S. H. (1995). Interactions of serotonin reuptake inhibitors with tricyclic antidepressants. Arch. Gen. Psychiat. 52:783–784.

    Google Scholar 

  • Heim, M., and Meyer, U. A. (1990). Genotyping of poor metabolizers of debrisoquine by allele-specific PCR amplification. Lancet 336:529–532.

    Google Scholar 

  • Hong, J., Pan, J., Gonzalez, F. J., Gelboin, H. V., and Yang, C. S. (1987). The induction of a specific form of cytochrome P450 (P-450j) by fasting. Biochem. Biophys. Res. Commun. 142:1077–1083.

    Google Scholar 

  • Honig, P. K., Wortham, D. C., Zamani, K., et al., (1993). Terfenadine-ketoconazole interaction. JAMA 269:1513–1518.

    Google Scholar 

  • Hooper, W. D., and Qing, M.-S. (1990). The influence of age and gender on the stereoselective metabolism and pharmacokinetics of mephobarbital in humans. Clin. Pharmacol. Ther. 48:633–640.

    Google Scholar 

  • Horsmans, Y., Desager, J. P., and Harvengt, C. (1992). Absence of CYP3A genetic polymorphism assessed by urinary excretion of 6-β hydroxycortisol in 102 healthy subjects on rifampicin. Pharmacol. Toxicol. 71:258–261.

    Google Scholar 

  • Hunt, C. M., Westerkam, W. R., and Stave, G. M. (1992). Effect of age and gender on the activity of human hepatic CYP3A. Biochem. Pharmacol. 44:275–283.

    Google Scholar 

  • Ieiri, I., Kubota, T., Urae, A., Kimura, M., Wada, Y., Mamiya, K., Yoshioka, S., Irie, S., Amamoto, T., Nakamura, K., Nakano., S., and Higuchi, S. (1996). Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, in Japanese subjects. Clin. Pharmacol. Ther. 59:647–653.

    Google Scholar 

  • Janicak, P. G., Javaid, J. I., Sharma, R. P., Comaty, J. E., Peterson, J., and Davis, J. M. (1989). Trifluoperazine plasma levels and clinical response. J. Clin. Psychopharmacol. 9:340–346.

    Google Scholar 

  • Kappas, A., Anderson, K. E., Conney, A. H., and Alvares, A. P. (1976). Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man. Clin. Pharmacol. Ther. 20:643–653.

    Google Scholar 

  • Kappas, A., Alvares, A. P., Anderson, K. E., Pantuck, E. J., Pantuck, C. B., Cahng, R., and Conney, A. H. (1978). Effect of charcoal-broiled beef on antipyrine and theophylline metabolism. Clin. Pharmacol. Ther. 23:445–450.

    Google Scholar 

  • Koop, D. R. (1992). Oxidative and reductive metabolism by cytochrome P450 2E1. FASEB J. 2:724–730.

    Google Scholar 

  • Krishna, D. R., and Klotz, U. (1994). Extrahepatic metabolism of drugs in humans. Clin. Pharmacokinet. 26:144–160.

    Google Scholar 

  • Kroemer, H. K., and Eichelbaum, M. (1995). Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sci. 56:2285–2298.

    Google Scholar 

  • Kunze, K. L., and Trager, W. F. (1996). Warfarin-fluconazole III: A rational approach to management of a metabolically based drug interaction. Drug Metab. Disp. 34:429–435.

    Google Scholar 

  • Kunze, K. L., Wienkers, L. C., Thummel, K. E., and Trager, W. F. (1996). Warfarin-fluconazole I: Inhibition of the human cytochrome P450-dependent metabolism of warfain by fluconazole: In vitro studies. Drug Metab. Disp. 34:412–421.

    Google Scholar 

  • Li, A. P., Kaminski, D. L., and Rasmussed, A. (1995). Substrates of human hepatic cytochrome P450 3A4. Toxicology 104:1–8.

    Google Scholar 

  • May, D. G., Wilkinson, G. R., and Branch, R. A. (1994). Frequency distribution of dapsone N-hydroxlase, a putative probe for P4503A4 activity, in a white population. Clin. Pharmacol. Ther. 55:492–500.

    Google Scholar 

  • Meyer, J. W., Woggon, B., Baumann, P., and Meyer, U. A. (1990). Clinical implications of slow sulphoxidation of thioridazine in a poor metabolizer of the debrisoquine type. Eur. J. Clin. Pharmacol. 39:613–614.

    Google Scholar 

  • Murray, M. (1992). P450 enzymes: Inhibition mechanisms, genetic regulation and effects of liver disease. Clin. Pharmacokinet. 23:132–146.

    Google Scholar 

  • Nafziger, N., and Bertino, J. S. (1989). Sex-related differences in theophylline pharmacokinetics. Eur. J. Clin. Pharmacol. 37:97–100.

    Google Scholar 

  • Nakamura, K., Goto, F., Ray, W. A., McAllister, C. B., Jacqz, E., Wilkinson, G. R., and Branch, R. A. 1985. Interethnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and European populations. Clin. Pharmacol. Ther. 38:402–408.

    Google Scholar 

  • Nebert, D. W., and Gonzales, F. J. (1987). P450 genes: Structure, evolution, and regulation. Annu. Rev. Biochem. 56:945–993.

    Google Scholar 

  • Nebert, D. W., Nelson, D. R., Coon, M. J., Estabrook, R. W., Feyereisen, R., Fujii-Kuriyama, Gonzalez, F. J., Guengerich, F. P., Gunsalas, I. C., Johnson, E. F., Loper, J. C., Sato, R., Waterman, M. R., and Waxman, D. J. (1991). The P450 superfamily; Update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol. 10:1–14.

    Google Scholar 

  • Nelson, D. R., Kamataki, T., Waxman, D. J., Guengerich, F. P., Estabrook, R. W., Feyerelsen, R., Gonzalez, F. J., Coon, M. J., Gunsalus, I. C., Gotoh, A., Okuda, K., and Nebert, D. W. (1993). The P450 superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol. 12:1–51.

    Google Scholar 

  • Nielsen, F., Rosholm, J.-U., and Brosen, K. (1995). Lack of relationship between quinidine pharmacokinetics and the spartein oxidation polymorphism. Eur. J. Clin. Pharmacol. 48:501–504.

    Google Scholar 

  • Omura, T., and Sato, R. (1962). A new cytochrome in liver microsomes. J. Biol. Chem. 237:PC1375-PC1376.

    Google Scholar 

  • Parkinson, A. (1996). An overview of current cytochrome P450 technology for assessing the safety and efficacy of new materials. Toxicol. Pathol. 24:45–57.

    Google Scholar 

  • Perrot, N., Nalpas, B., Yang, C. S., and Beaune, P. H. (1989). Modulation of cytochrome P450 isozymes in human liver, by ethanol and drug intake. Eur. J. Clin. Pharmacol. 19:549–555.

    Google Scholar 

  • Popli, A., Baldessarini, R. J., and Cole, J. O. (1995). Interactions of serotonin reptake inhibitors with tricyclic antidepressants—in reply. Arch. Gen. Psychiat. 52:784–785.

    Google Scholar 

  • Potkin, S. G., She, Y., Pardes, H., Phelps, B. H., Zhou, D., Shu, L., Korpi, E., and Wyatt, R. J. (1984) Haloperidol concentrations elevated in Chinese patients. Psychiatry Res. 12:167–172.

    Google Scholar 

  • Ratanasavanh, D., Beaune, P., Morel, F. et al. (1991). Intralobular distribution and quantitation of cytochrome P450 enzymes in human liver as a function of age. Hepatology 13:1142–1151.

    Google Scholar 

  • Relling, M. V., Lin, J.-S., Ayers, G. D., and Evans, W. E. (1992). Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin. Pharmacol. Ther. 52:643–658.

    Google Scholar 

  • Rodrigues, A. D. (1994). Use of in vitro human metabolism studies in drug development. Biochem. Pharmacol. 48:2147–2156.

    Google Scholar 

  • Rowland, M. (1975). Kinetics of drug-drug interactions. In Teorell, T., Dedrick, R. L., and Candliffe, P. G. (eds.), Pharmacology and Pharmacokinetics, Plenum Press, London, pp. 321–386.

    Google Scholar 

  • Rudorfer, M. V., Lane, E. A., Chang, W.-H., et al. (1984). Desipramine pharmacokinetics in Chinese and Caucasian volunteers. Br. J. Clin. Pharmacol. 17:433–440.

    Google Scholar 

  • Schuetz, J. D., Beach D. L., and Guzelian, P. S. (1994). Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics, 4:11–20.

    Google Scholar 

  • Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., Guengerich, F. P. (1994). Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals; studies with liver microsomes of 30 Japanese and 30 Caucausians. J. Pharmacol. Exp. Ther. 270:414–423.

    Google Scholar 

  • Spatzenegger, M., and Jaeger, W. (1995). Clinical importance of hepatic cytochrome P450 in drug metabolism. Drug Metab. Rev. 27:397–417.

    Google Scholar 

  • Spina, E., Ancione, M., Di Rosa, A. E., et al. (1992). Polymorphic debrisoquine oxidation and acute neuroleptic-induced adverse effects. Eur. J. Clin. Pharmacol. 42:347–348.

    Google Scholar 

  • Spina, E., Avenoso, A., Campo, G., Caputi, A. P., and Perucca, E. (1995). The effect of carbamazepine on the 2-hydroxylation of desipramine. Psychopharmacology 117:413–416.

    Google Scholar 

  • Vinarova, E., Vinar, O., and Kalvach, Z. (1984). Smokers need higher doses of neuroleptic drugs. Biol. Psychiat. 19:1265–1268.

    Google Scholar 

  • von Moltke, L. L., Greenblatt, D. J., Cotreau-Bibbo, M. M., Duan, S. X., Harmatz, J. S., and Shader, R. I. (1994a). Inhibition of desipramine hydroxylation in vitro by serotonin reuptake inhibitor antidepressants, and by quinidine and ketoconazole: A model system to predict drug interactions in vivo. J. Pharmacol. Exp. Ther. 268:1278–1283.

    Google Scholar 

  • von Moltke, L. L., Greenblatt, D. J., Cotreau-Bibbo, M. M., Harmatz, J. S., and Shader, R. I. (1994b). Inhibitors of alprazolam metabolism by serotonin reuptake inhibitor antidepressants, ketoconazole and quinidine. Br. J. Clin. Pharmacol. 38:23–31.

    Google Scholar 

  • von Moltke, L. L., Greenblatt, D. J., Harmatz, L. S., and Shader, R. I. (1994c). Cytochromes in psychopharmacology. J. Clin. Psychopharmacol. 14:1–4.

    Google Scholar 

  • von Moltke, L. L., Greenblatt, D. J., Court, M. H., Duan, S. X., Harmatz, J. S., and Shader, R. I. (1995). Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: Comparison with other selective serotonin reuptake inhibitor antidepressants. J. Clin. Psychopharmacol. 15:125–131.

    Google Scholar 

  • Walle, T., Walle, U. K., Cowart, T. D. et al. (1989). Pathway-selective sex differences in the metabolic clearance of propranolol. Clin. Pharmacol. Ther. 46:257–263.

    Google Scholar 

  • Waterman, M. R., Jenkins, C. M., and Pikuleva, I. (1995). Gentically engineered bacterial cells and applications. Toxicol. Lett, 82/83:807–813.

    Google Scholar 

  • Watkins, P. B., Murray, S. A., Winkelman, L. G., Heuman, D. M., Wrighton, S. A., and Guzelian, P. S. (1989). Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. J. Clin. Invest. 83:688–697.

    Google Scholar 

  • Wrighton, S. A., and Stevens, J. C. (1992). The human hepatic cytochromes P450 involved in drug metabolism. Crit. Rev. Toxicol. 22:1–21.

    Google Scholar 

  • Yang, C. S., Brady, J. F., and Hong, J.-Y. (1992). Dietary effects on cytochromes P450, xenobiotic metabolism, and toxicity. FASEB J. 6:737–744.

    Google Scholar 

  • Yue, O. Y., Svensson, J.-O, Alm, C., Sjoqvist, F., and Sawe, J. (1989). Interindividual and interethnic differences in the demethylation and glucuronidation of codeine. Br. J. Clin. Pharmacol. 28:629–637.

    Google Scholar 

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Glue, P., Clement, R.P. Cytochrome P450 Enzymes and Drug Metabolism—Basic Concepts and Methods of Assessment. Cell Mol Neurobiol 19, 309–323 (1999). https://doi.org/10.1023/A:1006993631057

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