CYTOCHROMES-P450 .8. HORMONAL-REGULATION OF HEPATIC-ENZYMES INVOLVED IN FOREIGN COMPOUND METABOLISM

The regulation of hepatic P450s has been the focus of numerous studies because of the importance of these proteins in endocrinology, oncolog y, and toxicology, as well as drug development. Considerable evidence exists demonstrating that many hepatic P450s are regulated by developm ental, sex, or hormonal factors in addition to receptors that interact with foreign chemicals. The focus of work in our laboratory has been on the effects of steroid hormones, especially glucocorticoids, on exp ression of genes regulated by the Ah receptor. We have shown that most rat hepatic genes of the Ah receptor gene battery are regulated by gl ucocorticoids. We have used glucocorticoid-deficient animal models to demonstrate that these steroids do modulate the expression (basal and inducible) of these genes in vivo. Using cultured rat hepatocytes, we have demonstrated that polycyclic aromatic hydrocarbon (PAH) induction of cytochrome P4501A1, glutathione S-transferase Ya(1), and UDP-glucu ronosyl-transferase 16 are apparently potentiated two- to fourfold up on inclusion of glucocorticoids in the media to activate the glucocort icoid receptor and further, that the receptor antagonist RU 38486 reve rses these phenomenon. NAD(P)H:quinone oxidoreductase and aldehyde deh ydrogenase 3 gene expression were repressed 70-80% by glucocorticoids in cultured hepatocytes through a glucocorticoid receptor-mediated pro cess as well. The effect of glucocorticoid concentration on PAH induct ion of glutathione S-transferase Ya(1) subunit for glucocorticoids was biphasic, but at physiological concentrations gene expression was rep ressed to similar to 20-40% of control. At supraphysiological concentr ations, glucocorticoids alone induced expression two- to threefold and potentiated the PAH-inducible expression of the Ya(1) subunit gene. S ubsequent work in our laboratory has focused on defining the molecular basis of this hormonal regulation, specifically elucidating responsiv e elements responsible for the action of the glucocorticoid receptor a nd the mechanisms by which some of these genes are positively regulate d and others are negatively regulated.