Drug-metabolizing enzymes, polymorphisms and interindividual response to environmental toxicants.
Individual risk of toxicity or cancer reflects the amount of exposure to environmental agents, combined with one's underlying genetic predisposition. More than six dozen human ecogenetic polymorphisms have been described; whereas some of these have been demonstrated to be associated with altered risks of toxicity or cancer, others presently remain equivocal and require further study. Thus, genetic differences in the regulation, expression and activity of "environmental susceptibility genes" can be decisive in defining susceptibility to toxicity or cancer. "Drug-metabolizing enzymes" (DMEs) are regarded as one class of environmental susceptibility genes. DME genes have actually existed on this planet for more than 2.5 billion years, and might more appropriately be named "effector-metabolizing enzymes." Receptors controlling DME levels have been called "DME receptors." DMEs have functioned in many critical life processes in prokaryotes and, more recently, in countless basic functions in plants and animals - events that evolved long before the existence of pharmaceutical companies and apothecaries. DME genes exist in every eukaryotic cell and probably in all prokaryotes. Virtually all environmental agents act as either agonists or antagonists - in competing with endogenous ligands that bind to DME receptors and/or competing as substrates for the DMEs. Over the past decade it has become clear that each of us has our own "individual fingerprint" of unique alleles coding for DMEs. The underlying genetic predisposition of each patient will reflect 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 lead to as much as 30- or >40-fold differences in activation or degradation. The end result can be large interindividual differences in risk of environmentally caused toxicity or cancer.
Nebert
D W
DW
Department of Pediatrics, University of Cincinnati Medical Center, Ohio 45267-0056, USA. dan.nebert@uc.edu
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004785:Environmental Pollutants; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009369:Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D010944:Plants / Q000378:metabolism; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014166:Transferases / Q000235:genetics / Q000378:metabolism
D004785:Environmental Pollutants; D003577:Cytochrome P-450 Enzyme System; D014166:Transferases