DEVELOPMENTAL PHARMACOGENETICS OF MICROSOMAL STEROID HYDROXYLASES

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Summary of Work: Metabolism by cytochromes P450 and specific transferases is a defense system against environmental toxicants and carcinogens. To encounter virtually unlimited numbers of structurally diverse xenochemicals, P450 and transferase genes are capable of being induced in response to the exposures to increase metabolic capability. Finding the induction mechanism is critical for our ability to predict human susceptability to xenochemical exposure. Phenobarbital (PB) is the prototype of a large number of chemicals that induce the sets of P450 and transferase genes. We have now defined the conserved 51-bp DNA found in these genes (in mouse, rat, and human) as the PB-responsive enhancer module or PBREM. We have also identified the nuclear orphan receptor CAR that activates PBREM in response to PB induction. PB induction was found to be defected in rats in which CAR function is impaired. In addition to numerous PB-type inducers, endgenous steroid hormones regulate the receptor CAR; estrogens are activators while androgens and progesterone are repressors. CAR is a cytosolic receptor in non-induced livers and translocates to nucleus following PB treatment. Establishing a system in which endodogenous CAR can be expressed in liver cells, we found that the C-terminal LXXLXXL sequence regulates the PB-inducible nuclear translocation of CAR.