Farmacologia

Pharmacology 2000;61:124–135

The Evolution of Drug Metabolism
Daniel W. Nebert Matthew Z. Dieter
Center for Environmental Genetics, Departments of Environmental Health and Pediatrics, University of Cincinnati, Medical Center, Cincinnati, Ohio, USA

Key Words Evolution of drug metabolism W Drug-metabolizing enzymes W Cytochrome P-450 W Pharmacogenetics W Pharmacogenomics W Animal-plantwarfare W Human DME polymorphisms W Molecular drive W Founder effect W Balanced polymorphisms W Single-nucleotide polymorphisms

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 prokaryotesand, 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-metabolizerphenotypes. 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 1 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 highfrequencies 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 drugmetabolism genes, but in all genes, and exhibiting large gene-by-gene variability.
Copyright © 2000 S. Karger AG, Basel

This special issue of Pharmacology is dedicated to Professor Elliot S. Vesell, dear friend of one coauthor (D.W.N.) and colleague who is retiring after having served 30 years as Editor of this journal. He has been a true pioneer, leader and early innovator in the field ofpharmacogenetics. Each article in this special issue focuses on different areas of novel technical advances in the field of pharmacogenetics, and how this field has recently evolved into pharmacogenomics. The main purpose of my paper is to provide a general discussion of why human pharmacogenetic differences might have developed initially.

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© 2000 S. Karger AG, Basel

Accessible online at: www.karger.com/journals/pha

D.W. Nebert, MD Center for Environmental Genetics Departments of Environmental Health and Pediatrics University of Cincinnati, Medical Center, PO Box 670056 Cincinnati, OH 45267-0056 (USA)

‘Pharmacogenetics’ is the study of the heritable basis of individual differences in response to pharmaceuticalagents [1, 2]. ‘Pharmacogenomics’, a recently introduced term, applies pharmacogenetic knowledge to information gained from The Human Genome Project – principally in pursuit of new drug design and discovery [3]. ‘Ecogenetics’ is the much broader field of the heritable basis of individual differences in response to all environmental chemical and physical agents (e.g. heavy metals, insecticides,compounds formed during combustion, ultraviolet radiation). This article is begun with personal reflections (of D.W.N.) on how he came to realize the far-reaching implications and importance of the evolution of drug metabolism. Next, we briefly review some of the latest findings in the field of DME research and how DMEs have evolved. We then emphasize the antiquity of these enzymes, from functioning...