The long-range goal of this project is to elucidate the biochemistry and regulation of hepatic cytochrome P450 (CYP) enzymes that oxidatively metabolize steroid hormones, cholesterol and other endogenous lipophilic compounds, using the rat as a model system. The proposed project period focused on the endocrine control of sex-specific steroid hydroxylase P450 enzymes, with special emphasis on the cellular and molecular mechanism(s) by which pituitary growth hormone (GH) and its sex- dependent ultradian secretory pattern differentially regulate the expression of male-specific and female-specific steroid hydroxylase P450s in rat liver. The male-specific testosterone 2alpha/16alpha- hydroxylase CYP2C11 and the female-specific steroid sulfate 15beta- hydroxylase CYP2C12 will be studied as prototypic examples of sexually dimorphic, GH pattern-regulated liver P450 genes. Studies carried out during the last project period led to the important discovery that the signal transducer and activator of transcription STAT5b is selectively activated by the pulsatile GH pattern associated with adult male pats, and is obligatory for establishing global male patterns of liver gene expression and whole body growth rates. The major objectives of the proposed project are: (1) to further elucidate the central role of STAT5b in GH pulse regulation of male-specific liver gene expression; (2) to fully characterize the intracellular events and signaling pathways that govern the repeated activation and deactivation of STAT5b by plasma GH pulses (STAT5b cycle); (3) to elucidate the mechanisms through which GH pulse-activated STAT5b signals to the nucleus to activate CYP2C11 transcription; and (4) to identify the mechanisms through which continuous GH regulates CYP2C12 expression, including a determination of the role of the female-expressed, GH-regulated nuclear factor, GHNF in this process. These studies will provide a basic understanding, at the cellular and molecular level, of some of the key mechanisms whereby GH and its sexually dimorphic plasma profiles regulate the expression of an important family of enzymes that controls metabolic processes having a major impact on liver physiology and human health, including steroid hormone metabolism, cholesterol degradation, drug biotransformation and carcinogen activation.
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