The long-range goal of this project is to provide a detailed understanding of the biochemistry and regulation of hepatic P450 enzymes that oxidatively metabolize steroid hormones, cholesterol and other endogenous lipophilic compounds, using the rat as a model system. The proposed project period focuses on two specific areas: pituitary control of sex-specific steroid hydroxylase P450 enzymes, and regulation of P450 cholesterol 7alpha- hydroxylase (P450 Ch7alpha), which catalyzes the first and rate limiting step in the degradation of cholesterol to bile acids. The major objectives of this project are to: (1) elucidate the molecular mechanism(s) by which serum growth hormone and its sex-dependent ultradian secretory pattern differentially regulate the expression of male-specific and female-specific steroid hydroxylase P450s in rat liver, (2) identify age- and hormone- dependent transcription factors that regulate the expression of the male- specific testosterone 2alpha/16alpha-hydroxylase P450 2c (gene IIC11), as well as the DNA regulatory elements with which these factors interact, (3) establish the mechanisms for both long-term and short-term regulation of hepatic cholesterol 7alpha-hydroxylase activity in response to dietary, circadian and hormonal factors and (4) isolate and sequence a cloned cDNA encoding P450 Ch7alpha in order to facilitate more detailed studies on the structure and regulation of this key enzyme of cholesterol catabolism. These studies will lead to a basic understanding, at the molecular level, of some of the mechanisms whereby pituitary hormones regulate the expression of hepatic steroid and drug metabolizing enzymes. They will also further our understanding of the metabolic pathways leading to cholesterol degradation and bile acid biosynthesis, and may thereby suggest useful biochemical approaches to the control of a number of pathological conditions, including atherosclerosis and cholesterol gallstones.
Showing the most recent 10 out of 114 publications
