Abstract
There are pronounced interindividual and interethnic differences in the capacity to metabolize drugs and other xenobiotics. This variation is due to genetic polymorphism of the corresponding genes, as well as to physiological-, environmental- and pathological factors. From a teleological point of view it is evident that genetically based interindividual variability is seen in the human lymphocyte antigen (HLA) system, the immune system and in the inherited defences towards infection by malaria or tuberculosis and that this creates survival of some part of the population during infectious epidemics. In an analogous manner the variability in the drug metabolizing system will be beneficial for survival during chemical catastrophes. In this overview I will focus on the genetic aspects of the drug metabolizing enzymes with emphasis on some P450 forms and the mechanistic basis for their variability. The methods for predicting the genotype of a certain individual and on the possible use of this information in the future will also be considered.
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
Agúndez, J.A.G, Ledesma, M.C, Ladero, J.M. and BenÃtez, J. (1995) Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin Pharmacol Ther 57:265–269.
Albano, E., Clot, P., Morimoto, M., Tornasi, A., Ingelman-Sundberg, M. and French, S. (1995) Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol. Hepatology 23:155–163.
Aklillu, E., Persson, I., Bertilsson, L., Johansson, I., Rodrigues, F. and Ingelman-Sundberg, M. (1996) Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharm Exp Ther 278:441–446.
Bertilsson, L., Dahl, M.-L., Sjöqvist, F., Åberg-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.
Bertilsson, L., Dahl, M.-L., Ingelman-Sundberg, M., Johansson, I. and Sjöqvist, F. (1995) Inter individual and interethnic differences in polymorphic drug oxidation - implications for drug theraphy with focus on psychoactive drugs. In: Advances in Drug Metabolism in Man, (Pacifici, G. and Fracchia, G.N., Eds), EUR 15439 EN, EC, DGXII-E-4, Luxembourg, office for publications of the European Commission, pp. 85–136.
Clot, P., Albano, E., Eliasson, E., Tabone, M., Arico, S., Israel, Y., Moneada, C. and Ingelman-Sundberg, M. (1996) Cytochrome P4502E1 (CYP2E1) hydroxyethyl radical adducts as the major antigenic determinants for autoantibody formation among alcoholics. Gastroenterology 111: 206–216.
Gram, L.F., Brösen, K., Sindrup, S and Skjelbo, E (1995) Genetic and interethnic variability in drug metabolism: What are the clinical consequences. In: European Conference on Specificity and Variability in Drug Metabolism, (Alván, G., Balant, L.P., Bechtel, P.R., Boobis, A., Gram, L.F., Paintaud, G. and Pithan, K., Eds) COST B1, Luxembourg: Office for Official Publications of the European Communities EU, pp. 235–245.
Dahl, M.-L., Johansson, I., Bertilsson, L., Ingelman-Sundberg, M. and Sjöqvist F. (1995) Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J Pharmacol Exp Ther 274:516–520.
Eliasson, E., Johansson, I. and Ingelman-Sundberg, M. (1990) Substrate, hormone and cAMP- regulated cytochrome P450 degradation, Proc. Natl. Acad. Sci (USA) 87: 3225–3229.
Eliasson, E., Mkrtchian S, and Ingelman-Sundberg, M. (1992) Hormone- and substrate regulated intracellular degradation of cytochrome P450 (2E1) involving MgATP-activated rapid proteolysis in the endoplasmic reticulum membranes J Biol Chem 267:15765–15769.
Heim, M.H. and Meyer, U.A. (1990) Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 336:529–532.
Hu, Y., Johansson, I., Yun, Q-Y and Ingelman-Sundberg, M. (1996) Genetic polymorphism of the human CYP2E1 gene. Characterization of two variant alleles present in Caucasian and Chinese populations. Mol Pharmacol, in press.
Ingelman-Sundberg, M. and Johansson, I. (1995) The molecular genetics of the human drug metabolizing cytochrome P450S. In: Advances in Drug Metabolism in Man, (Pacifici, G. and Fracchia, G.N., Eds), EUR 15439 EN, EC, DGXII-E-4, Luxembourg, Office for Publications of the European Comission, pp. 543–586.
Ingelman-Sundberg, M., Johansson, I., Hu, Y., Terelius, Y., Eliasson, E., Clot, P., and Albano, E. (1993) Ethanol-inducible cytochrome P4502E1: Genetic polymorphism, regulation and possible role in the etiology of alcohol-induced liver disease. Alcohol 10:447–452.
Johansson, I., Bertilsson, L., Dahl, M-L, Sjöqvist, F and Ingelman-Sundberg, M. (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci (USA) 90:11825–11829.
Johansson, I., Yue, Q.-Y., Dahl, M.-L., Heim, M., Säwe, J., Bertilsson, L., Meyer, U.A, Sjöqvist, F, and Ingelman-Sundberg, M. (1991) Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine. Eur J Clin Pharmacol 40: 553–556.
Ingelman-Sundberg, M., Johansson, I., Hu, Y., Terelius, Y., Eliasson, E., Clot, P., and Albano, E. (1993) Ethanol-inducible cytochrome P4502E1: Genetic polymorphism, regulation and possible role in the etiology of alcohol-induced liver disease. Alcohol 10:447–452.
Johansson, I., Oscarson, M., Yue, Q.-Y., Bertilsson, L., Sjöqvist, F. and Ingelman-Sundberg, M. (1994) Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 46:452–459.
Masimirembwa, C.M., Johansson, I., Hasler, J.A. and Ingelman-Sundberg, M. (1993) Genetic polymorphism of cytochrome P450 CYP2D6 in a Zimbabwean population. Pharmacogenetics 3:275–280.
Masimirembwa, C.M., Persson, I., Bertilsson, L., Hasler, J.A. and Ingelman-Sundberg, M. (1996a) Diminished enzyme activity and lack of metabolic coregulation of CYP2D6 probe drugs in a black Zimbabwean population. Eur J Clin Pharmacol, in press.
Masimirembwa, C.M., Persson, I., Bertilsson, L., Hasler, J.A. and Ingelman-Sundberg, M. (1996b) Molecular basis of diminished debrisoquine hydroxylase (CYP2D6) activity in a black African population: A common mutation in exon 2 of the CYP2D6 gene. Br J Clin Pharmacol, in press.
McLellan, R.A., Oscarson, M., Seidegård, J., Price Evans, D.A. and Ingelman-Sundberg, M. (1996) Frequent occurrence of CYP2D6 gene duplication in Saudi Arabia, Pharmacogenetics, in press.
Morimoto, M., Hagbjörk, A.-L., Yvonne- Y-J., Fu, P.C. Albano, E. Ingelman-Sundberg, M. and French, S.W. (1995) Modulation of alcoholic liver disease by cytochrome P450 2E1 inhibitors, Hepatology 21:1610–1617.
Oscarson M, Hidestrand M, Johansson I, Masimirembwa CM, Hasler JA, Ingelman-Sundberg M. (1996) Detrimental effect of combined mutations in the CYP2D6Z (2D6*i7) allele. XIth International Symposium on Microsomes and Drug Oxidations, Los Angeles, p. 214.
Rannug, A., Alexandrie, A-K., Persson, I and Ingelman-Sundberg, M. (1995) Genetic polymorphism of cytochrome P450 1A1, 2D6 and 2E1. Regulation and toxicological significance. J Occ Env Med 37:25–36.
Ronis, M.J.J., Lindros, K.O. and Ingelman-Sundberg, M. (1996) The cytochrome P4502E subfamily. In: Cytochromes P450, Pharmacological and Toxicological Aspects (Ioannides, I., Ed.) CRC Press, pp. 211–239.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1997 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Ingelman-Sundberg, M. (1997). Genetic Polymorphism of Drug Metabolizing Enzymes. Implications for Toxicity of Drugs and Other Xenobiotics. In: Seiler, J.P., Vilanova, E. (eds) Applied Toxicology: Approaches Through Basic Science. Archives of Toxicology, vol 19. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60682-3_1
Download citation
DOI: https://doi.org/10.1007/978-3-642-60682-3_1
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-64505-1
Online ISBN: 978-3-642-60682-3
eBook Packages: Springer Book Archive