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.
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.
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