EXCEED THE SPACE PROVIDED. The long-range goal of this project is to elucidate the biochemistry and regulation of hepatic cytochrome P450 (CYP) enzymes that catalyze oxidative metabolism of steroid hormones, drags, carcinogens and other lipophilic substrates of medical or environmental importance. The proposed project period uses the rat as a model system and focuses on pituitary control of sex-specific steroid hydroxylase P450 enzymes. Special emphasis is placed on the cellular and molecular mechanisms by which plasma growth hormone (GH) and its sex-dependent ultradian secretory patterns regulate the expression of sex-specific steroid hydroxylase P450s in rat liver. The rat liver P450 enzymes CYP2C11 (a testosterone 2c_- and 16o_-hydroxylase) and CYP2A2 (a testosterone 15o_-hydroxylase) will be studied as prototypic examples of distinct classes of male-specific, GH pattern-regulated liver P450 genes. The proposed studies will test the hypothesis that the sex-dependent expression of liver P450 enzymes involves the cooperative interaction of hepatocyte-enriched nuclear transcription factors (HNFs) with signal transducer and activator of transcription STAT5b, a transcription factor that is strongly activated by the pulsatile GH pattern specifically found in adult male rats. The major objectives of the proposed project are: (1) to elucidate the mechanisms whereby GH-responsive HNFs cooperate with STAT5b to regulate the male-specific liver CYPs 2C 11 and 2A2; (2) to investigate the mechanisms by which GH regulates liver transcription factors, with a focus on novel post-transcriptional regulatory paradigms involving HNF3[3 and HNF4, both of which contribute to the transcriptional regulation ot the GH-responsive, male-specific liver CYPs; (3) to employ global liver mRNA expression profiling to identify novel sexually dimorphic GH target genes, including genes that may contribute to the unique response of liver CYPs to the sex-dependent temporal patterns of plasma GH stimulation; and (4) to utilize comparative proteomic methods to identify rat liver nuclear proteins whose abundance or state of post-translational modification is regulated by the sex-dependent plasma GH profile, and which may contribute to GH regulation of liver CYP gene expression. These studies will help elucidate the key cellular and molecular mechanisms whereby GH and its sexually dimorphic plasma profiles regulate the expression of cytochrome P450, 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, drag biotransformation and carcinogen activation. PERFORMANCE SITE ========================================Section End===========================================
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