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Genetic polymorphism of cytochrome P450. Functional consequences and possible relationship to disease and alcohol toxicity

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Toward a Molecular Basis of Alcohol Use and Abuse

Part of the book series: Experientia ((EXS,volume 71))

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Summary

The hepatic cytochrome P450 system participates in the oxidative metabolism of numerous endogenous and exogenous compounds. In total several hundred different P450s have been cloned, but it appears that in humans only about 5–10 isoforms account for the major part of drug metabolism. Some of these are polymorphically distributed in the population. Cytochrome P450 2D6 catalyzes the oxidation of over 25 clinically important drugs, eg neuroleptics, antidepressants and lipophilic β-blockers. Seven % of Caucasians and 1% of Orientals are defective in this enzyme and clearance of drugs metabolized by the enzyme may be substantially decreased in these individuals, with potentially increased risks for side effects caused by the drug treatment. Some individuals are ultrarapid metabolizers and do not achieve therapeutic drug levels at ordinary doses. The molecular genetic basis of these polymorphisms are presented. Methods for genotyping, which can be of predictive value for a more efficient drug therapy, are discussed. Ethanol-inducible cytochrome P450 2E1 (CYP2E1) oxidizes ethanol and acetaldehyde, in addition to over 80 toxicologically important xenobiotics. Furthermore, this isozyme produces reactive oxy radicals which are implicated in the aetiology of alcoholic liver disease. The gene is polymorphic and a mutation in a putative binding site for HNF1, described to affect gene expression, is more rare among subjects with lung cancer as compared to healthy controls. Further studies might give an answer as to whether any of the polymorphic CYP2E1 alleles is associated with the sensitivity to obtain alcoholic liver disease.

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Authors and Affiliations

  1. Department of Medical Biochemistry and Biophysics, Karolinska institutet, S-171 77, Stockholm, Sweden

    M. Ingelman-Sundberg, I. Johansson, I. Persson, M. Oscarson, Y. Hu, L. Bertilsson, M.-L. Dahl & F. Sjöqvist

  2. Department of Medical Laboratory Sciences and Technology, Karolinska institutet, Huddinge University Hospital, S-141 86, Huddinge, Sweden

    L. Bertilsson, M.-L. Dahl & F. Sjöqvist

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  1. M. Ingelman-Sundberg
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  2. I. Johansson
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  3. I. Persson
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  4. M. Oscarson
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  5. Y. Hu
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  6. L. Bertilsson
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  7. M.-L. Dahl
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  8. F. Sjöqvist
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Editor information

Editors and Affiliations

  1. Department of Psychiatry, Karolinska Institutet, Huddinge University Hospital, S-141 86, Huddinge, Sweden

    B. Jansson

  2. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden

    H. Jörnvall

  3. Department of Clinical Neuroscience, Karolinska Institutet, S-171 76, Stockholm, Sweden

    U. Rydberg  & L. Terenius  & 

  4. Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Seeley G. Mudd Building, 250 Longwood Avenue, 02115, Boston, MA, USA

    B. L. Vallee

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© 1994 Birkhäuser Verlag Basel/Switzerland

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Ingelman-Sundberg, M. et al. (1994). Genetic polymorphism of cytochrome P450. Functional consequences and possible relationship to disease and alcohol toxicity. In: Jansson, B., Jörnvall, H., Rydberg, U., Terenius, L., Vallee, B.L. (eds) Toward a Molecular Basis of Alcohol Use and Abuse. Experientia, vol 71. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-7330-7_20

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  • DOI: https://doi.org/10.1007/978-3-0348-7330-7_20

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-0348-7332-1

  • Online ISBN: 978-3-0348-7330-7

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