Inherent Sexually Dimorphic Expression of Hepatic CYP2C12 Correlated with Repressed Activation of Growth Hormone-Regulated Signal Transduction in Male Rats

Abstract

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 cAMPresponse element-binding protein, and hepatocyte nuclear factors 4␣ 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.

GH signaling in skeletal muscle and adipose tissue in healthy human subjects: impact of gender and age

“…This is in accordance with the data obtained in primary hepatocytes from male and female rats (27). In the latter study, pSTAT5 following episodic GH exposure was more pronounced in male hepatocytes.…”

“…A total of 20 normal-weight subjects (meanGS.E.M., BMI: 25G2) comprising ten 'young' subjects (5F/5M) with a mean (range) age of 25 (20)(21)(22)(23)(24)(25)(26)(27)(28) years and ten 'old' subjects (5F/5M) with a mean age of 65 (60-72) years participated in this study. None were smokers or receiving prescribed drugs, and none of the females received estrogen supplementation.…”

Sex Differences of Drug-metabolizing Enzyme: Female Predominant Expression of Human and Mouse Cytochrome P450 3A Isoforms

“…Recruitment and/or activation levels of all component factors in the pathway were highly suppressed in male hepatocytes, possibly explaining this difference. 87) Consistent with this finding, the induction of Cyp3a41 and Cyp3a44 gene expression after exposure to continuous GH is prominent in female-derived hepatocytes and not observed in male-derived cells. 65) In contrast, although femalederived hepatocytes will respond to male episodic GH, the response is inherently limited, i.e., responses are more prominent in male-derived than female-derived hepatocytes.…”

“…85,86) Thus, studies of this gene provided various suggestions. With respect to the signaling cascade activated by feminine continuous GH secretion, Thangavel and Shapiro recently proposed elements in that pathway, 87) growth hormone receptor (GHR), extracellular signal-regulated kinase (Erk), the cAMPresponse element-binding protein (CBP), and hepatocyte nuclear factors 4α and 6, in their likely order of activation. In other words, continuous GH induces CYP2C12 expression by activating Erk1 and Erk2 via GHR, which in turn activates nuclear CBP, which acetylates HNF4α and HNF6, which then bind to the CYP2C12 promoter, contributing to the gene's transcription.…”

Transcriptional Regulation of Cytochrome P450 Genes by the Nuclear Receptor Hepatocyte Nuclear Factor 4-Alpha

“…These authors discovered that HNF4 is a major factor for regulating the expression of the CYP2C12 gene when it cooperates with HNF6, STAT5 and other factors. The important role of HNF4 and HNF6 in the regulation of CYP2C12 in females has been further demonstrated in a recent study using primary hepatocytes derived from male and female hypophysectomized rats [68]. However, these studies do not agree with a previous work, which suggested that HNF4 is not a major trans-activator in the rat CYP2C12 and other CYP2C genes [28].…”