Hormonal Imprinting Predetermines Developmental Expression of Cytochrome P450s

描述（由申请方提供）：在研究的所有种属（包括人类）中细胞色素P450的个体发育表达表明存在印迹。每个P450亚型通过“程序化”的发育阶段进行，最终在成人表达模式中达到顶峰，其特征在于永久抑制许多雌雄同体的不成熟形式的P450和永久诱导在成人中观察到的大多数性二态水平的P450。尽管所有的两性异形都被证明是由睾酮或其代谢产物所印记的，但类固醇似乎对P450个体发育没有发育影响。由于组织的形态和功能的分化是由相同的激素，负责其在成年期的监管，和生长激素（GH），而不是雄激素，仅调节性二态表达的肝P450在所有物种的检查，我们提出，生长激素不可逆地印记发展中的肝P450系统。使用一种高效的GH拮抗剂，我们计划检查印记的影响，在关键的新生期P450个体发育的激素通过评估受影响的成年雄性和雌性大鼠的性别依赖性P450亚型的表达。我们还计划研究GH在限制肝脏表达异性同种型的能力方面的印记效应。最后，由于发展的肝脏P450系统的特点是抑制大多数亚型，直到青春期，我们已经提出，他们的最终外观是依赖于个体发育的信号转导途径调节其表达。我们选择检查调节显性雄性特异性CYP 2C 11表达的JAK/STAT信号传导途径以及调节显性雌性特异性CYP 2C 12表达的ERK/CBP/HNF信号转导途径的发展。为了阐明GH印记性别依赖性肝脏P450的机制，我们将检查经GH阻断的大鼠中这些信号传导途径的发育概况，以确定与正常的任何畸变。像所有的性二态性一样，肝脏P450的表达最多只能部分性别逆转。为了确定这种反应的原因，我们将比较两种性别的两种信号通路对GH激活的个体发生反应。预期，我们的研究将确定发育机制，决定成人模式的P450表达和性别依赖性药物代谢的起源。 公共卫生相关性：本研究拟通过研究分化酶系统的激素印记和调节成人P450亚型表达的信号转导途径的个体发生来阐明细胞色素P450药物代谢的个体发生调节机制。内分泌系统或信号通路的发育中断，这两种常见的药物靶点，可能会导致药物代谢的永久性改变，在制定儿童药物治疗时应予以考虑。最后，我们建议确定药物代谢中性别差异的起源，这对于理解基于性别的药物生物分布至关重要。

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.