ENDOGENOUS REGULATORS OF DRUG METABOLISM

这项建议的广泛目标是调查机制(S) 生长激素(GH)通过什么来调控性二型性 肝细胞色素P450亚型(P450；CYP)的表达 这影响了最近提出的关于性别的担忧- 治疗剂的有效性。在确定了根本的 性二型血浆生长激素谱中的“信号”元素 原始性器官的转录和/或翻译- 依赖P450，我们现在建议通过以下方式来研究其机制(S 肝细胞识别并区分 生长激素及其转导系统中的性二型信号 给原子核的信息。我们假设不同的 细胞外信号在循环生长激素谱中的差异 调节生长激素受体的结合动力学和/或转位 (Ghr)，进而激活特定的信号转导通路 负责启动选择性性别的转录- 依赖的P450亚型。由于男性特有的CYP2C11和 雌性特异性(CYP2C12是主要的大鼠亚型 高达50%的总肝脏P450含量的性别， 我们已经确定了所需的基本生长激素信号 对于它们的选择性表达，我们选择了如下的异构体 以下研究中的原型。我们计划专门恢复 生长激素耗竭雌性大鼠肝脏细胞色素P4502C12的表达 生长激素耗竭雄性大鼠体内注射细胞色素P450受体C11的表达 我们所认定的选择性有效的性别- 依赖生长激素谱以识别信号分子 参与他们的监管。 成人肝脏P450蛋白的表达水平与性别相关 而无论用什么方法处理，雄鼠都不能诱导出 表达肝脏P450的完整女性模式，女性也不能 治疗后表现出正常的男性模式。我们假设这是 成体激素非依赖性且不可逆的反应 围产期(如雄激素或雌激素)或青春期(如性行为) 类固醇或生长激素)激素，导致对 一种性别对性别依赖性的信号转导途径 异性的血浆生长激素谱。为了检验这一假设，我们 计划在大鼠中检测依赖P450的信号转导通路 注射了相反的性别特定的血浆GH图谱。最后， 我们计划测试我们的假设，即围产期和/或青春期 荷尔蒙将不可逆的、性别相关的反应性印在 CYP2C11和2C12对生长激素的调节作用 在印迹期间消融假定的荷尔蒙 GH诱导性反转的亚型可塑性评价 成人期。

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.