Sexually Dimorphic Regulation of Hepatic Isoforms of Human Cytochrome P450 by Growth Hormone

Dhir, Ravindra; Dworakowski, Wojciech; Thangavel, Chellappagounder; Shapiro, Barry A.

doi:10.1124/jpet.105.093773

Cited by 79 publications

(81 citation statements)

References 38 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since HYPOX depletes the body of at least a dozen hormones, including, not just GH, but those of the thyroid, adrenal and gonads, it isn't possible without far more experiments, to determine which hormones may induce or suppress CYP2C11 in the immune system of both male and female rats. In this regard, thyroid hormone is required for full expression of several hepatic P450s [45], androgens are the primary regulators of kidney CYP2C11 in rats [46] and hepatic P450-dependent enzymes in chickens [47] and glucocorticoids are essential for expression of human CYP3A4 [48].…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

Thangavel

Dhir

Volgin

et al. 2007

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

CYP2C11, the most commonly expressed isoform of cytochrome P450 in male rat liver, was measured in spleen, thymus and bone marrow by quantitative real-time PCR and enhanced Western blotting. CYP2C11 concentrations in the lymphoid tissues were a fraction of that observed in liver, but like the liver, were sexually dimorphic (M>F) with mRNA and protein levels in agreement. Although the response to hypophysectomy varied according to tissue and sex, expression levels of CYP2C11 in all measured tissues remained greater in males. Further differences in CYP2C11 expression between liver and lymphoid tissue were observed following restoration of the circulating masculine growth hormone profile in hypophysectomized rats. In contrast to the liver where the renaturalized growth hormone profile elevated CYP2C11 expression in both sexes, the response was opposite in spleen and thymus with isoform concentrations declining in both sexes. Lastly, the divergent response of CYP2C11 between the liver and immune system was examined in cultured splenocytes exposed to different mitogens. In contrast to the dramatic depletion of CYP2C11 reported in proliferating hepatocytes, mitogen-stimulation resulted in a significant elevation in splenocyte CYP2C11 expression. In summary, we report for the first time that thymus, spleen and bone marrow express, albeit nominal, sex-dependent levels of CYP2C11 (M>F) whose regulation appears to be under some hormonal control, but very different from that of the hepatic isoform.

show abstract

Section: Discussionmentioning

confidence: 99%

Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

Thangavel

Dhir

Volgin

et al. 2007

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previously it has been reported that CYP2E1, 3A4, 1A2, 2A6, and 2B6 are subject to gender influence in humans, but conflicting results have been obtained (Dhir et al 2006;Anderson 2008;Scandlyn et al 2008). Our results support that the activity of CYP3A4 (but not the others reported) is affected by gender, with females having higher activity measurement than males.…”

Section: Discussionmentioning

confidence: 99%

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

Yang¹,

Zhang²,

Molony³

et al. 2010

Genome Res.

236

222

View full text Add to dashboard Cite

Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.

show abstract

“…These sex differences in the circulating GH profiles and not sexual differences in GH concentrations per se are responsible for observed sexual dimorphisms ranging from body growth to the expression of hepatic enzymes (Jansson et al, 1985;Legraverend et al, 1992;Shapiro et al, 1995). In this regard, rat, murine, and human liver all contain sexdependent isoforms of P450 that are regulated by the sex-dependent profiles of circulating GH (Legraverend et al, 1992;Shapiro et al, 1995;Dhir et al, 2006). Sex-dependent, hepatic P450s in the rat are generally divided into three groups: male-specific isoforms only found in male liver, femalespecific isoforms only expressed in female liver, and sex (generally female)-predominant P450s found in both sexes, but at higher levels in one sex.…”

mentioning

confidence: 99%

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

Thangavel

Shapiro²

2008

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Sexually Dimorphic Regulation of Hepatic Isoforms of Human Cytochrome P450 by Growth Hormone

Cited by 79 publications

References 38 publications

Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

Sex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

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

Contact Info

Product

Resources

About