The P450 family of enzymes plays important roles in the metabolism of drugs, carcinogens, steroid hormones, and environmental/occupational chemicals (1-5). P4501A1 and P4501A2, two members of the 1A family, catalyze oxygenation of PAHs and HAAs, as well as dealkylation of phenacetin and caffeine. The reactions serve as initial steps in the conversion of chemicals to more polar metabolites for excretion from the body and thus represent an adaptive response to changes in the chemical environment of cells. On the other hand, oxygenation of carcinogenic PAH and HAA (procarcinogens) can generate arene oxide, dioepoxide, and other electrophilic reactive species (ultimate carcinogens), leading to tumor formation or cell toxicity (6-8). The formation of more toxic or carcinogenic species as a result of metabolism is known as metabolic activation. Humans are exposed to carcinogens from a variety of sources, such as tobacco smoke, automobile exhaust, smoked and cooked food, and industrial processes. High levels of exposure to PAHs and HAAs contribute to increased incidence of cancer in certain populations such as smokers (6,9). Because of the unique role of P4501A enzymes in the metabolic activation of carcinogens, variations in P4501A activities in human tissues can, in principle, influence the susceptibility of individuals to chemical carcinogenesis.
Qiang Ma, Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV