ENDOGENOUS REGULATORS OF DRUG METABOLISM

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The broad objective of this proposal is to investigate the mechanism(s) by which growth hormone (GH) regulates the sexually dimorphic expression of hepatic isoforms of cytochrome P450 (P450; CYP), which impacts on recently raised concerns regarding the gender- effectiveness of therapeutic agents. Having identified the fundamental elements in the sexually dimorphic plasma GH profiles that "signal" the transcription and/or translation of the primary rat constitutive sex- dependent P450s, we now propose to examine the mechanism(s) by which the hepatocyte recognizes and discriminates between the sexually dimorphic signals in the GH profiles and transduces their messages to the nucleus. We hypothesize that the different extracellular signals in the circulating GH profiles differentially regulate binding kinetics and/or translocation of the GH receptor (GHR) which in turn activates specific signal transduction pathways responsible for initiation the transcription of selective gender- dependent isoforms of P450. Since male-specific CYP2C11 and female-specific (CYP2C12 are the primary rat isoforms representing up to 50% of the total hepatic P450 content in their respective sexes, and we have already identified the fundamental GH signals required for their selective expression, we have chosen these isoforms as prototypes in the following studies. We plan to specifically restor hepatic CYP2C12 expression in GH-depleted female rats and CYP2C11 expression in GH-depleted male rats by infusing them with what we have determined to be the selectively effective gender- dependent GH profiles in order to identify the signaling molecules involved in their regulation. Expression levels of hepatic P450s are gender-dependent in the adult rat and regardless of the treatment, males can not be induced to express the full female pattern of hepatic P450s nor can females be treated to express the normal male pattern. We hypothesize that this adult hormone-independent and -irreversible response in imprinted by perinatal (e.g. androgens or estrogens) or peripubertal (e.g. sex steroids or GH) hormones that result in a reduced responsiveness of signal transduction pathways in one sex to the gender-dependent plasma GH profiles of the opposite sex. To test this hypothesis we plan to examine P450-dependent signal transduction pathways in rats infused with the opposite gender-specific plasma GH profiles. Lastly, we plan to test our hypothesis that perinatal and/or peripubertal hormones imprint the irreversible, sex-dependent responsiveness of CYP2C11 and 2C12 to GH regulation by administering or selectively ablating the presumptive hormones during the imprinting period and evaluating the plasticity of the isoforms to GH-induced sex reversal in adulthood.