Carcinogen metabolism and individual susceptibility.
Many chemical carcinogens need activation by drug metabolizing enzymes, principally cytochrome P450 enzymes, to become capable of binding to deoxyribonucleic acid and initiating the carcinogenic process. The activity and inducibility of drug metabolizing enzymes are regulated by interplay between genetic, host, and environmental factors. Consequently, individual differences in cancer susceptibility might be explained somewhat by genetic differences in metabolic activation. Three examples, the induction of aryl hydrocarbon (benzo[a]pyrene) hydroxylase by polycyclic aromatic hydrocarbons, polymorphic debrisoquine/sparteine oxidation, and polymorphic acetylation, are briefly reviewed. Despite useful animal models and promising early human findings, no consensus has been reached about the significance of genetically based differences in drug metabolism in cancer etiology. It is expected that, with the use of molecular biological methods, the genetic background of study subjects can be investigated without bias caused by the disease, age, treatment, or other factors which have plagued investigations thus far.
Pelkonen
O
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Department of Pharmacology and Toxicology, University of Oulu, Finland.
D000107:Acetylation; D000818:Animals; D000983:Antipyrine / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism; D005544:Forecasting; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D008660:Metabolism / Q000235:genetics; D011110:Polymorphism, Genetic; D013034:Sparteine / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism
D002273:Carcinogens; D013034:Sparteine; D001189:Aryl Hydrocarbon Hydroxylases; D000983:Antipyrine; D003647:Debrisoquin