Hormonal Imprinting Predetermines Developmental Expression of Cytochrome P450s

描述（由申请人提供）：细胞色素p450在包括人类在内的所有研究物种中的个体表达表明印记。每个P450异构体都经历了“程序化”的发育阶段，最终形成成人表达模式，其特征是永久性抑制许多雌雄同体的未成熟P450形式，永久性诱导在成人中观察到的大部分两性二态P450水平。尽管所有的两性二态性都被证明是由睾酮或其代谢物所影响的，但类固醇似乎对P450个体发育没有影响。由于组织形态和功能的分化是由成年期负责调节的同一激素决定的，并且生长激素（GH），而不是雄激素，在所有研究的物种中仅调节肝脏P450的两性二态表达，我们提出生长激素不可逆转地影响发育中的肝脏P450系统。使用一种高效的生长激素拮抗剂，我们计划通过评估受影响的成年雄性和雌性大鼠中性别依赖的P450亚型的表达，来检查激素在P450个体发育的关键新生期的印记效应。我们还计划研究生长激素在限制肝脏表达异性同种异构体能力方面的印记效应。最后，由于肝脏P450系统的发育特点是在青春期之前抑制大多数亚型，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。我们选择了JAK/STAT信号通路调控显性雄性特异性CYP2C11的表达，以及ERK/CBP/HNF信号通路调控显性雌性特异性CYP2C12的表达。为了阐明GH印记性别依赖性肝脏p450的机制，我们将在新生儿GH阻断大鼠中检查这些信号通路的发育特征，以确定与正常情况下的任何异常。像所有的两性异形一样，肝脏p450的表达最多只能部分逆转性别。为了确定这种反应的原因，我们将比较两种性别的信号通路对生长激素激活的个体反应性。预期，我们的研究将确定发育机制，决定P450的成人表达模式和性别依赖性药物代谢的起源。

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.