Hormonal Imprinting Predetermines Developmental Expression of Cytochrome P450s

描述(申请人提供)：细胞色素P450在所有被研究物种中的个体表达，包括人类，是印记的迹象。每一种P450亚型都经历了“程序化”的发育阶段，最终形成成体的表达模式，其特征是许多雌雄同体的不成熟P450被永久抑制，而在成人中观察到的P450主要是性二态水平的P450被永久诱导。尽管所有的性二型都被证明受到睾酮或其代谢物的影响，但类固醇似乎对P450个体发育没有影响。由于一个组织的形态和功能的分化是由成年期负责调节它的相同激素决定的，而生长激素(GH)，而不是雄激素，在所有被研究的物种中只调节肝脏P450的性别二型性表达，我们认为GH不可逆转地印记正在发育的肝脏P450系统。使用一种高效的生长激素拮抗剂，我们计划通过评估性别依赖的P450亚型在受影响的成年雄性和雌性大鼠中的表达，来检测该激素在P450个体发育的关键新生时期的印记效应。我们还计划研究生长激素在限制肝脏表达异性异构体的能力方面的印记效应。最后，由于肝脏P450系统的发育是以抑制大多数异构体直到青春期为特征的，我们提出它们的最终出现取决于调节其表达的信号转导途径的个体发生。我们选择研究JAK/STAT信号通路和ERK/CBP/HNF信号转导通路的发展，其中JAK/STAT信号通路调节男性占优势的CYP2C11的表达，ERK/CBP/HNF信号转导通路调节女性占优势的CYP2C12的表达。为了阐明GH印记性别依赖的肝脏P450的机制(S)，我们将在新生GH阻断的大鼠中检测这些信号通路的发育概况，以确定是否存在与正常大鼠不同的异常。像所有的性二型一样，肝脏P450的表达充其量只能部分性别颠倒。为了确定这种反应的原因，我们将比较两性两种信号通路对GH激活的个体反应。不出所料，我们的研究将确定决定成人P450表达模式的发育机制，以及性别依赖性药物代谢的起源。 公共卫生相关性：该研究建议通过检查分化酶系统的激素印迹和调节成人P450亚型表达的信号转导通路的个体发生，来揭示调节细胞色素P450药物代谢的个体发生的机制。内分泌系统或信号通路的发育障碍是两种常见的药物靶点，都可能导致药物代谢的永久性变化，在制定儿童药物疗法时应予以考虑。最后，我们建议确定药物代谢中性别差异的根源，这对于理解药物基于性别的生物处置至关重要。

DESCRIPTION (provided by applicant): The ontogenic expression of cytochrome P450s in all species studied, including humans, is indicative of imprinting. Each P450 isoform proceeds through "programmed" stages of development culminating in an adult pattern of expression characterized by the permanent suppression of many androgynous immature forms of P450 and permanent induction of mostly sexually dimorphic levels of P450s observed in adults. Whereas all sexual dimorphisms have been shown to be imprinted by testosterone or its metabolites, the steroids appear to have no developmental effect on P450 ontogeny. Since the differentiation of a tissue's morphology and function is determined by the same hormone responsible for its regulation in adulthood, and growth hormone (GH), not androgens, solely regulates the sexually dimorphic expression of hepatic P450s in all species examined, we have proposed that GH irreversibly imprints the developing hepatic P450 system. Using a highly potent GH antagonist, we plan to examine the imprinting effects of the hormone during the critical neonatal period of P450 ontogeny by evaluating the expression of sex-dependent P450 isoforms in affected adult male and female rats. We also plan to study the imprinting effects of GH in limiting the liver's ability to express the isoforms of the opposite sex. Lastly, since the development of the hepatic P450 system is characterized by the suppression of most isoforms until puberty, we have proposed that their eventual appearance is dependent upon the ontogenesis of the signal transduction pathways regulating their expression. We have chosen to examine the development of the JAK/STAT signaling pathway regulating expression of the dominant male- specific CYP2C11 as well as the ERK/CBP/HNF signal transduction pathway regulating expression of the dominant female-specific CYP2C12. In order to elucidate the mechanism(s) by which GH imprints the sex- dependent hepatic P450s, we will examine the developmental profiles of these signaling pathways in neonatally GH-blocked rats to identify any aberrations from the normal. Like all sexual dimorphisms, expression of the hepatic P450s can at best be only partially sex-reversed. In order to identify the cause of this response, we will compare the ontogenic responsiveness of both signaling pathways in both sexes to GH activation. Expectedly, our studies will identify developmental mechanisms that determine adult patterns of P450 expression and the origins of sex-dependent drug metabolism. PUBLIC HEALTH RELEVANCE: The research proposes to unravel mechanisms regulating the ontogenesis of cytochrome P450-drug metabolism by examining hormonal imprinting of the differentiating enzyme system and the ontogenesis of the signal transduction pathways regulating expression of adult P450 isoforms. Developmental disruption of the endocrine system or signaling pathways, both common drug targets, could result in permanent alterations in drug metabolism and should be considered in formulating drug therapies for children. Lastly, we propose to identify the origins of sex differences in drug metabolism, essential in understanding the sex-based biodisposition of drugs.