Induction of cytochrome P4501A1.

Cytochrome P4501A1 is a substrate-inducible microsomal enzyme that oxygenates polycyclic aromatic hydrocarbons, such as the carcinogen benzo(a)pyrene, as the initial step in their metabolic processing to water-soluble derivatives. Enzyme induction reflects increased transcription of the cognate CYP1A1 gene. The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin is the most potent known cytochrome P4501A1 inducer. Two regulatory proteins, the aromatic (aryl) hydrocarbon receptor (AhR) and the AhR nuclear translocator (Arnt), mediate induction. AhR and Arnt are prototypical members of the basic helix-loop-helix/Per-Arnt-Sim class of transcription factors. Mechanistic analyses of cytochrome P4501A1 induction provide insights into ligand-dependent mammalian gene expression, basic helix-loop-helix/Per-Arnt-Sim protein function, and dioxin action; such studies also impact public health issues concerned with molecular epidemiology, carcinogenesis, and risk assessment.