A STAT FACTOR MEDIATES THE SEXUALLY DIMORPHIC REGULATION OF HEPATIC CYTOCHROME-P450 3A10 LITHOCHOLIC ACID 6-BETA-HYDROXYLASE GENE-EXPRESSION BY GROWTH-HORMONE/

Adult male rodents have a pulsatile profile of growth hormone (GH) rel ease, whereas female rodents have a relatively steady-state pattern wi th uniform, albeit lower levels of GH. The expression of a number of s exually differentiated hepatic proteins is primarily determined by the se plasma GH profiles and only secondarily regulated by gonadal hormon es. An important subset of these sexually dimorphic proteins is cytoch rome P450s. CYP3A10/6 beta-hydroxylase is a cytochrome P450 that catal yzes the 6 beta-hydroxylation of lithocholic acid. CYP3A10/6 beta-hydr oxylase is expressed only in male hamsters; however, mimicking the mal e GH secretion pattern in females induces expression of the gene to ma le levels, Using chimeric CYP3A10/6 beta-hydroxylase promoter/lucifera se reporter genes transfected into hamster primary hepatocytes, we hav e shown a GH-mediated induction of promoter activity. A combination of 5'-deletion constructs, heterologous promoter constructs, and specifi c mutagenesis was used to localize the DNA element involved in the GH- mediated regulation of CYP3A10/6 beta-hydroxylase promoter activity, w hich resembles a STAT binding site. Footprint and gel shift analyses c onfirmed that the expression of the protein binding to this site is re gulated by GH and that the DNA-protein complex can be partially supers hifted by anti-STAT-5 antibodies. This protein is 50% more abundant in male than in female hamster livers, is absent in hypophysectomized fe male livers, and is restored when hypophysectomized females are inject ed with GH in a manner that masculinizes female hamsters in terms of C YP3A10/6 beta-hydroxylase expression. The system characterized and des cribed here is ideally suited for dissecting the molecular details gov erning the sexually dimorphic expression of liver-specific genes.