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Vol. 61, No. 3, 2000
Issue release date: September 2000
Pharmacology 2000;61:124–135
(DOI:10.1159/000028393)

The Evolution of Drug Metabolism

Nebert D.W. · Dieter M.Z.
Center for Environmental Genetics, Departments of Environmental Health and Pediatrics, University of Cincinnati, Medical Center, Cincinnati, Ohio, USA

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Abstract

So-called ‘drug-metabolizing enzyme’ (DME) genes have existed on this planet for more than 2.5 billion years and would be more appropriately named ‘effector-metabolizing enzymes’. Genes encoding DMEs have functioned in many fundamental processes in prokaryotes and, more recently, in countless critical life processes in plants and animals. DME genes exist in every eukaryotic cell and in most, if not all, prokaryotes. Over the past decade, it has become clear that each person has their own ‘individual fingerprint’ of unique alleles coding for DMEs. The underlying genetic predisposition of each patient reflects combinations of poor- and extensive-metabolizer phenotypes. If these enzymes cooperate in the same metabolic pathway for any given drug or environmental agent, such ecogenetic variability might be synergistic and could cause 30- to >40-fold differences in activation or degradation. The end result can be large interindividual differences in risk of environmentally caused toxicity or cancer. Human DME gene polymorphisms often show high frequencies of variant alleles. Many factors contribute to persistence of these high frequencies, including a combination of selective pressures involving diet, climate and geography, as well as ‘balanced polymorphisms’ (‘shared benefit’ for the heterozygote). However, the extensive heterogeneity in the human genome currently being discovered suggests many more polymorphisms will occur not only in drug metabolism genes, but in all genes, and exhibiting large gene-by-gene variability.

Copyright © 2000 S. Karger AG, Basel



Copyright / Drug Dosage

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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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