Enodgenous Regulators of Drug Metabolism

点击翻译按钮获取中文摘要

The broad objective of this proposal is to investigate the mechanisms by which growth hormone (GH) regulates the sexually dimorphic expression of hepatic isoforms of cytochrome P450 (CYP), which impacts on concerns regarding the gender- effectiveness of therapeutic agents. Having identified the basic elements in the masculine "episodic" and feminine "continuous" plasma GH profiles that selectively "signal" the expression of 8 constitutive sex-dependent rat CYPs, we now propose to examine the mechanisms by which the hepatocyte discriminates between the numerous GH signals and transduces their messages to the nucleus. We hypothesize that each extracellular signal in the circulating GH profiles activates a different signal transduction pathway responsible for the induction or suppression of each isoform. We propose to identify the different signal transduction pathways mediating GH regulation of CYPs by both infusing GH-devoid rats and exposing primary rat hepatocytes to individual GH signals known to regulate expression of each CYP isoform. Similar experiments will be conducted to identify GH-dependent CYP isoforms in human hepatocytes and the signal transduction pathways mediating their action. Expression levels of hepatic CYPs are gender-dependent in the adult rat (as well as in every other species examined), and regardless of the treatment, males can not be induced to express the full female pattern of hepatic CYPs nor can females be treated to express normal male patterns. We propose to investigate whether the sexually dimorphic CYP isoforms are permanently imprinted by determining the degree of CYP sex reversal in gender crossed (male to female and female to male) hepatocyte transplants. Follow-up studies will examine gender- based imprinting differences in the signal transduction responses to GH signals.