DEVELOPMENTAL PHARMACOGENETICS OF MICROSOMAL STEROID HYDROXYLASES

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Summary of Work: Metabolism by cytochromes P450 is a defense system against environmental toxicants and carcinogens. Consequently, the metabolic capability affects human susceptability to xenochemical exposure. To encounter virtually unlimited numbers of structurally diverse xenochemicals, P450 genes are capable of being induced in response to the exposures. Thus, finding the induction mechanism is critical for our ability to predict the susceptibility to xenochemicals. Using mouse primary hepatocytes, we have defined a 51-bp DNA found in the human CYP2B gene as the phenobarbital-responsive enhancer module or PBREM. We have also identified the nuclear orphan receptor CAR as a phenobarbital-responsive transcription factor that activates PBREM and induces the CYP2B gene. CAR is a cytosolic receptor in non-induced livers and translocates to nucleus following treatment by phenobarbital. The CAR nuclear translocation is an initial regulatory step in induction by phenobarbital of the CYP2B gene. CAR and PBREM are conserved in mouse, rat and human and can respond to not only phenobarbital but also numerous phenobarbital-type inducers, indicating their functional versatility. - Cytochrome P450, Gene regulation, Nuclear receptor, Drug metabolism, Induction, Phenobarbital