Abstract
Because of its myriad physiologic functions, it is not surprising that the actions of growth hormone (GH) are mediated by recruiting/activating dozens of signaling molecules involved in numerous transduction pathways. The particular signal transduction pathway activated by the hormone is determined by the affected target cell, the sexually dimorphic secretory GH profile (masculine episodic or feminine continuous) to which the cell is exposed, and the individual's sex. In this regard, expression of female-specific CYP2C12, the most abundant cytochrome P450 in female rat liver, is solely regulated by the feminine GH profile. Sex is a modulating factor in this response in that males are considerably less responsive than females to the CYP2C12-induction effects of continuous GH. Using primary hepatocytes derived from male and female hypophysectomized rats, we have identified several factors in a transduction pathway activated by the feminine GH regime and associated with the induction of hepatic CYP2C12. Elements in the proposed pathway, in their likely order of activation, are the growth hormone receptor, extracellular signal-regulated kinases, the cAMP-response element-binding protein, and hepatocyte nuclear factors 4α and 6, which subsequently bind and activate the CYP2C12 promoter. Recruitment and/or activation levels of all of the component factors in the pathway were highly suppressed in male hepatocytes, possibly explaining the dramatically lower induction levels of CYP2C12 in males exposed to the same continuous GH profile as females.
Footnotes
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↵1 Similar, although less dramatic, intrinsic sex differences in expression levels of CYP3A4 and CYP1A2 regulated by the sex-dependent GH profiles have been reported in human hepatocytes (Dhir et al., 2006).
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↵2 Continuous exposure of female rat primary hepatocytes to as little as 0.2 ng/ml GH was sufficient to both induce and maintain CYP2C12 mRNA and protein at 40 to 60% of levels induced by a hormone concentration 10 times higher (Thangavel et al., 2004).
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↵3 Although it is possible that male hepatocytes metabolize GH more quickly than female hepatocytes, this is certainly not the case in vivo (Pampori and Shapiro, 1999). Moreover, increasing the concentration of GH in the media by 10-fold to 20 ng/ml had no significant effect on the sexually dimorphic ratio of induced CYP2C12 (unpublished observation).
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This work was supported in part by National Institutes of Health Grant GM-45758 and the Chutzpah Foundation.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.021451.
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ABBREVIATIONS: GH, growth hormone; P450, cytochrome P450; Jak, Janus kinase; Stat, signal transducer and activator of transcription; IB, immunoblotting; Erk, extracellular signal-regulated kinase; HNF, hepatocyte nuclear factor; MAPK, mitogen-activated protein kinase; GHR, growth hormone receptor; GHRL, full-length GHR; GHRS, short-form GHR; IP, immunoprecipitation; CBP, cAMP response element-binding protein; ChIP, chromatin immunoprecipitation; bp, base pair(s); PCR, polymerase chain reaction; G6PDH, glucose-6-phosphate dehydrogenase; F, female; M, male.
- Received March 12, 2008.
- Accepted June 12, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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