Overview of enzymes of drug metabolism
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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.
Key Wordsdrug metabolism interindividual variation cytochrome P450 induction genetic polymorphism in vitro prediction
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- 1.P. R. Ortiz de Montellano (ed.).Cytochrome P450. Structure, Mechanism, and Biochemistry, Plenum Press, New York, 1995.Google Scholar
- 3.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).PubMedCrossRefGoogle Scholar
- 4.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.Google Scholar
- 6.W. Kalow, H. W. Goedde, and D. P. Agarwal.Ethnic Differences in Reactions to Drugs and Xenobiotics, AR Liss, New York, 1986.Google Scholar
- 8.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).PubMedCrossRefGoogle Scholar
- 12.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.Google Scholar
- 16.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).Google Scholar
- 17.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).PubMedCrossRefGoogle Scholar