ENDOGENOUS REGULATORS OF DRUG METABOLISM

本提案的总体目标是调查机制 生长激素（GH）通过其调节性二态性 细胞色素P450（P450; P450）的肝同种型的表达， 这影响到最近提出的关于性别问题的关切- 治疗剂的有效性。 在确定了基本的 性二态血浆GH谱中的"信号"元素 原代大鼠组成性性别的转录和/或翻译- 依赖性P450，我们现在建议通过以下方式检查机制： 肝细胞识别并区分 性二态信号在生长激素档案和转导他们的 向细胞核发送信息。 我们假设， 循环GH谱中的细胞外信号差异 调节GH受体的结合动力学和/或易位 (GHR)进而激活特定的信号传导途径 负责启动选择性性别的转录- P450的依赖性亚型。 由于男性特异性CYP2C11和 雌性特异性（CYP2C12是主要的大鼠同种型， 在其各自性别中高达肝脏P450总含量的50%， 我们已经确定了所需的基本GH信号 对于它们的选择性表达，我们选择这些异构体作为 原型在以下研究中。 我们计划专门恢复 GH耗竭雌性大鼠肝脏CYP2C12表达， 通过向GH耗竭的雄性大鼠输注CYP2C11表达 我们已经确定了选择性有效的性别- 依赖GH谱，以鉴定信号分子 参与其监管。 成人肝脏P450表达水平具有性别依赖性 大鼠和无论处理，雄性不能诱导 表达肝脏P450的完全女性模式， 被用来表现正常的男性特征 我们假设这 成年人的非依赖性和不可逆的反应，在印迹 围产期（如雄激素或雌激素）或青春期（如性别 类固醇或生长激素）激素，其导致 信号转导途径在一个性别的性别依赖 异性的血浆GH谱。 为了验证这一假设， 计划在大鼠中检测P450依赖的信号转导通路 输注相反性别特异性血浆GH曲线。 最后， 我们计划验证我们的假设，即围产期和/或青春期 激素会使人产生不可逆的、依赖于性别的反应， CYP2C11和2C12通过给药或选择性给药对GH的调节 在印记期间消除假定的激素， 评估同种型对GH诱导的性逆转的可塑性， 成年

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.