Overview of enzymes of drug metabolism
- Urs A. Meyer
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Most pharmacologically active molecules are lipophilic and remain un-ionized or only partially ionized at physiological pH. Biotransformation means that a lipid-soluble xenobiotic or endobiotic compound is enzymatically transformed into polar, water-soluble, and excretable metabolites. The major organ for drug biotransformation is the liver. The metabolic products often are less active than the parent drug or inactive. However, some biotransformation products (metabolites) may have enhanced activity or toxic effects. Thus biotransformation may include both “detoxication” and “toxication” processes. One of the major enzyme systems that determines the organism's capability of dealing with drugs and chemicals is represented by the cytochrome P450 monooxygenases. Studies in the last 15 years have provided evidence that cytochrome P450 occurs in many different forms or “isozymes” which differ in spectral, chemical, and immunological properties and have different substrate affinities. These isozymes also differ in their regulation and tissue distribution. Recombinant DNA studies indicate that between 40 and 60 structural genes code for different cytochrome P450 isozymes in a single organism. Other enzyme systems include dehydrogenases, oxidases, esterases, reductases, and a number of conjugating enzyme systems including glucuronosyltransferases, sulfotransferases, glutathione S-transferases, etc. Environmental and genetic factors cause interindividual and intraindividual differences in drug metabolism and may alter the balance between toxification and detoxification reactions. Genetic polymorphisms lead to subpopulations of patients with decreased, absent, or even increased activities of certain reactions (e.g., CYP2D6, CYP2C19, N-acetyltransferase polymorphism). Environmental factors such as other drugs, steroids, dietary factors, alcohol, and cigarette smoke can induce or inhibit drug-metabolizing enzymes and cause intraindividual variation.
- P. R. Ortiz de Montellano (ed.).Cytochrome P450. Structure, Mechanism, and Biochemistry, Plenum Press, New York, 1995.
- M. Pirmohamed, N. R. Kitteringham, and B. K. Park. The role of active metabolites in drug toxicity.Drug Safety 11:114–144 (1994).
- D. R. Nelson, T. Kamataki, D. J. Waxman, F. P. Guengerich, R. W. Estabrook, R. Feyereisen, F. J. Gonzalez, M. J. Coon, I. C. Gunsalus, O. Gotoh, K. Okuda, and D. W. Nebert. The P450 superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature.DNA Cell Biol. 12:1–51 (1993).
- U. A. Meyer, R. C. Skoda, U. M. Zanger, M. Heim, and F. Broly. The genetic polymorphism of debrisoquine/sparteine metabolism-molecular mechanisms. In W. Kalow (ed.),Pharmacogenetics of Drug Metabolism, Pergamon, New York, 1992, pp. 609–623.
- U. A. Meyer. Commentary. Pharmacogenetics: The slow, the rapid, and the ultrarapid.Proc. Natl. Acad. Sci. U.S. 91:1983–1984 (1994).
- W. Kalow, H. W. Goedde, and D. P. Agarwal.Ethnic Differences in Reactions to Drugs and Xenobiotics, AR Liss, New York, 1986.
- M. Heim and U. A. Meyer. Genotyping of poor metabolizers of debrisoquine by allele-specific PCR amplification.Lancet 336:529–532 (1990). CrossRef
- F. Broly, D. Marez, N. Sabbagh, M. Legrand, S. Millecamps, J.-M. Lo Guidice, P. Boone, and U. A. Meyer. An efficient strategy for detection of known and new mutations of the CYP2D6 gene using single strand conformation polymorphism analysis.Pharmacogenetics 5:373–384 (1995).
- S. M. F. De Morais, G. R. Wilkinson, J. Blaisdell, K. Nakamura, U. A. Meyer, and J. A. Goldstein. The major genetic defect responsible for the polymorphism ofS-mephenytoin metabolism in humans.J. Biol. Chem. 269:15419–15422 (1994).
- S. M. F. De Morais, G. R. Wilkinson, J. Blaisdell, U. A. Meyer, K. Nakamura, and J. A. Goldstein. Identification of new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese.Mol. Pharmacol. 46:594–598 (1994).
- U. A. Meyer and U. M. Zanger. Molecular mechanisms of genetic polymorphisms of drug metabolism.Annu. Rev. Pharmacol. Toxicol. 37: 269–296 (1997). CrossRef
- A. B. Okey. Enzyme induction in the cytochrome P450 system. In W. Kalow (ed.),Pharmacogenetics of Drug Metabolism, Pergamon, New York, 1992, pp. 549–608.
- D. J. Waxman and L. Azaroff. Phenobarbital induction of cytochrome P450 gene expression.Biochem. J. 281:577–592 (1992).
- J. P. Whitlock, Jr. Mechanistic aspects of dioxin action.Chem. Res. Toxicol. 6:754–763 (1993). CrossRef
- J. George, M. Murray, K. Byth, and G. C. Farrell. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease.Hepatology 21:120–128 (1995). CrossRef
- P. J. Meier, H. K. Mueller, B. Dick, and U. A. Meyer, Hepatic monooxygenase activities in subjects with a genetic defect in drug oxidation.Gastroenterology 85:682–692 (1993).
- T. Kronbach, V. Fischer, and U. A. Meyer. Cyclosporine metabolism in human liver: Identification of a cytochrome P450 of the P450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs.Clin. Pharmacol. Ther. 43:630–635 (1988).
- T. Kronbach, D. Mathys, M. Umeno, F. J. Gonzalez and U. A. Meyer. Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4.Mol. Pharmacol. 36:89–96 (1989).
- T. Andersson, J. O. Miners, M. E. Veronese, W. Tassaneeyakul, W. Tassaneeyakul, U. A. Meyer, and D. J. Birkett. Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism.Br. J. Clin. Pharmacol. 36:521–530 (1993).
- F. P. Guengerich, D. Müller-Enoch, and I. A. Blair. Oxidation of quinidine by human liver cytochrome P-450.Mol. Pharmacol. 30:287–295 (1986).
- R. Fonne-Pfister and U. A. Meyer. Xenobiotic and endobiotic inhibitors of cytochrome P450db1 function, the target of the debrisoquine/sparteine type polymorphism.Biochem. Pharmacol. 37:3829–3835 (1988). CrossRef
- Overview of enzymes of drug metabolism
Journal of Pharmacokinetics and Biopharmaceutics
Volume 24, Issue 5 , pp 449-459
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- drug metabolism
- interindividual variation
- cytochrome P450
- genetic polymorphism
- in vitro prediction
- Industry Sectors
- Urs A. Meyer (1)
- Author Affiliations
- 1. Department of Pharmacology, Biozentrum of the University of Basel, Klingelbergstrasse 70, CH-4056, Basel, Switzerland