Abstract
Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups in the population which differ in their ability to perform a certain drug biotransformation reaction. Genetic polymorphisms thus contribute considerably to interindividual variation in drug response. Individuals with genetically impaired metabolism are usually designated as poor metabolizers, as compared to normal or extensive metabolizers.
This research was supported by Swiss National Science Foundation grant 3.817.87 and by an MRC Canada fellowship to D. M. G.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Beaune P, Dansette PM, Mansuy D, Kiffel L, Finck M, Amar C, Leroux JP, Homberg JC (1987) Human anti-endoplasmic reticulum autoantibodies appearing in a drag-induced hepatitis are directed against a human liver cytochrome P450 that hydroxylates the drug. Proc Natl Acad Sci USA 84: 551–555
Dayer P, Kronbach T, Eichelbaum M, Meyer UA (1987) Enzymatic basis of the debriso- quine/sparteine-type genetic polymorphism of drug oxidation. Biochem Pharmacol 36: 4145–4152
Eichelbaum M (1984) Polymorphic drug oxidation in humans. Fed Proc 43: 2298–2302
Eichelbaum M, Baur MP, Dengler HJ, Osikowska-Evers BO, Tieves G, Zekorn C, Rittner C (1987) Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22. Br J Clin Pharmacol 23: 455
Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, Nebert DW, Gelboin HV, et al. (1988) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331: 442–446
Grant DM, Tang BK, Kalow W (1984) A simple test for acetylator phenotype using caffeine. Br J Clin Pharmacol 17: 459–464
Gut J, Catin T, Dayer P, Kronbach T, Zanger U, Meyer UA (1986 a) Debriso- quine/sparteine-type polymorphism of drug oxidation: purification and characterization of two functionally different human liver cytochrome P450 isozymes involved in impaired hydroxylation of the prototype substrate bufuralol. J Biol Chem 261: 1 1734
Gut J, Meier UT, Catin T, Mayer UA (1986 b) Mephenytoin-type polymorphism of drug oxidation: purification and characterization of a human liver cytochrome P-450 isozyme catalyzing microsomal mephenytoin hydroxylation. Biochim Biophys Acta 884: 435–447
Jacqz E, Hall SD, Branch RA, Wilkinson GR (1986) Polymorphic metabolism of mephenytoin in man. Pharmacokinetic interaction with a co-regulated substrate, mephobarbital. Clin Pharmacol Ther 39: 646–653
Kronbach T, Mathys D, Gut J, Catin T, Meyer UA (1987) High performance liquid chromatographic assays for bufuralol l’-hydroxylase, debrisoquine 4-hydroxylase, and dextromethorphan O-demethylase in microsomes and purified cytochrome P-450 isozymes of human liver. Anal Biochem 162: 24–32
Küpfer A, Preisig R (1983) Inherited defects of hepatic drug metabolism. Semin Liver Dis 3: 341–354
Meier UT, Meyer UA (1987) Genetic polymorphism of human cytochrome P450 S- mephenytoin-4-hydroxylase. Biochemistry 26: 8466–8474
Meier UT, Kronbach T, Meyer UA (1985) Assay of mephenytoin metabolism in human liver microsomes by high-performance liquid chromatography. Anal Biochem 151: 286–291
Meier UT, Dayer P, Male PJ, Kronbach T, Meyer UA (1986) Mephenytoin hydroxylation polymorphism: characterization of the enzymatic deficiency in liver microsomes of poor metabolizers phenotyped in vivo. Clin Pharmacol Ther 38: 488–494
Meyer UA (1987) Polymorphisms of human drug metabolising enzymes. In: Benford DJ, Bridges JW, Gibson GG (eds) Drug metabolism - from molecules to man. Taylor and Francis, London, pp 95–105
Skoda RC, Gonzalez FJ, Demierre A, Meyer UA (1988) Two mutant alleles of the human cytochrome P450dbl-gQm associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci USA 85: 5240–5243
Weber WW, Hein DW (1985) N-acetylation pharmacogenetics. Pharmacol Rev 37: 25–79
Zanger UM, Vilbois F, Hardwick JP, Meyer UA (1988 a) Absence of hepatic cytochrome P450bufl causes genetically deficient debrisoquine oxidation in man. Biochemistry 27: 5447–5454
Zanger UM, Hauri HP, Loeper J, Homberg JC, Meyer UA (1988 b) Antibodies against human cytochrome P450dbl in autoimmune hepatitis type II. Proc Natl Acad Sci USA 85: 8256–8260
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1989 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Meyer, U.A., Zanger, U., Skoda, R., Grant, D.M. (1989). Genetic Polymorphisms of Drug-Metabolizing Enzymes: Molecular Mechanisms. In: Dahl, S.G., Gram, L.F. (eds) Clinical Pharmacology in Psychiatry. Psychopharmacology Series, vol 7. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-74430-3_15
Download citation
DOI: https://doi.org/10.1007/978-3-642-74430-3_15
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-74432-7
Online ISBN: 978-3-642-74430-3
eBook Packages: Springer Book Archive