Inadequacy of the Janus Kinase 2/Signal Transducer and Activator of Transcription Signal Transduction Pathway to Mediate Episodic Growth Hormone-Dependent Regulation of Hepatic CYP2C11

Verma, Ajay; Dhir, Ravindra; Shapiro, Barry A.

doi:10.1124/mol.104.005454

Cited by 27 publications

(32 citation statements)

References 34 publications

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“…Although this proposed pathway includes several elements not previously identified in continuous GH induction of CYP2C12 (e.g., Erk1, Erk2, and CBP), it certainly does not preclude other factors, some of which might be associated with different signaling pathways regulating CYP2C12 expression. The occurrence of multiple or redundant pathways is not uncommon in biologic systems and could explain contradictory findings regarding mechanisms of P450 expression (Verma et al, 2005).…”

Section: Sex Differences In Cyp2c12 Responses To Ghmentioning

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

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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.

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Section: Sex Differences In Cyp2c12 Responses To Ghmentioning

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

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“…The bulk of each liver mince was processed by the method of Sierra et al (1993) with minor modifications (Verma et al, 2005). In brief, minced livers were homogenized in buffer containing different protease and phosphatase inhibitors.…”

Section: Methodsmentioning

confidence: 99%

“…We used 1.5-mm, 10% SDS-polyacrylamide gels for CYP2C11, CYP3A2, IB-␣, Stat5A, Stat5B, and activated MAPK and 4 to 10% gradient gels (SDS-polyacrylamide gel electrophoresis) for phospho-Jak2. Western blot analyses were performed as reported previously (Verma et al, 2005). The blots were analyzed with an FluorChem 8800 gel documentation system (Alpha Innotech, San Leandro, CA) using a visible light source.…”

Section: Methodsmentioning

confidence: 99%

“…One microgram of RNA from each sample was reverse-transcribed in a 20-l reaction volume. One microliter of cDNA was PCRamplified according to our previous description (Verma et al, 2005). PCR primers for CYP2C11, CYP3A2 (Morris and Davila, 1996), and CYP2A1 (Geng and Strobel, 1993) were synthesized by Sigma-Genosys (The Woodlands, TX).…”

Section: Methodsmentioning

confidence: 99%

“…That is, regardless of the restored GH profile, female hepatocytes, either in vitro or in vivo (Legraverend et al, 1992;Shapiro et al, 1993;Waxman et al, 1995;Thangavel et al, 2006) cannot express male-like levels of male-specific P450s, nor can male hepatocytes, either in vitro (Thangavel et al, 2004) or in vivo (Pampori and Shapiro, 1999) be induced to express female-like levels of female-dependent P450s. Accordingly, regulation of male-specific CYP2C11 by episodic GH appears to involve the activation of the Janus kinase (Jak2)/signal transducers and activators of transcription (Stat5B) pathway (Waxman and O'Connor, 2006), in addition to other possible signaling pathways, such as mitogen-activated protein kinase (MAPK) (Verma et al, 2005) and nuclear factor-B (NF-B) (Iber et al, 2000), which are examined here as the basis for the inherent sex-dependent response of CYP2C11 to episodic GH.…”

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confidence: 99%

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Attenuated Expression of Episodic Growth Hormone-Induced CYP2C11 in Female Rats Associated with Suboptimal Activation of the Jak2/Stat5B and Other Modulating Signaling Pathways

Dhir

Thangavel²,

Shapiro

2007

Drug Metab Dispos

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ABSTRACT:Inherent sex differences in various parameters of growth, musculoskeletal function, metabolism, and cytochrome P450 (P450)-dependent drug metabolism have been reported in rats and humans administered typical intermittent/episodic growth hormone (GH) replacement therapy. Having infused and monitored the identical physiologic masculine (episodic) growth hormone profile to both hypophysectomized male and female rats, we observed that induction levels of hepatic CYP2C11 were 35 to 40% lower in females. Associated with the reduced expression of the P450 isoform in the episodic GH-treated females were dramatically lower activation levels of Janus kinase (Jak2), signal transducers and activators of transcription (Stat5A and 5B) as well as 50% less binding of Stat5B to the CYP2C11 promoter. Because the Jak2/ Stat5B signaling pathway mediates the effects of the masculine GH profile on its target cells, we conclude that the lower induction level of CYP2C11 in females exposed to the masculine GH profile is probably due, at least in part, to the suboptimum activation of the Jak2/Stat5B pathway. In addition to the reduced activation of the Jak2/Stat5B pathway, we observed lower activational levels of mitogen-activated protein kinase (p44/p42) and, indirectly, nuclear factor-B in the episodic GH-treated females that may be involved in attenuating the activity of the Jak2/Stat5B pathway diminishing CYP2C11 expression levels.

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Sex Differences in Drug Metabolism

Chang

Waxman

2012

Encyclopedia of Drug Metabolism and Interactions

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Sex differences in drug metabolism are recognized as a major determinant of sex differences in pharmacokinetics and an important contributor to interindividual differences in drug metabolism and, in some cases, drug action. Sex differences in human drug metabolism have also been observed with a variety of drugs. The biochemical basis of sex differences in hepatic drug metabolism was largely unknown until the 1980s when it was discovered that the expression of many drug‐metabolizing enzymes, including several members of the cytochrome P450 (CYP) superfamily, is sex dependent in rat and mouse liver. Well‐studied examples include rat enzymes CYP2C11, which is male specific in its expression, and CYP2C12 (female specific) and CYP2A1 (female predominant). The major gonadal hormones, testosterone and estradiol, regulate the sex‐dependent expression of rat hepatic CYP enzymes indirectly, through their effects on the hypothalamus and its regulation of the sexually dimorphic, ultradian rhythm of pituitary growth hormone (GH) secretion, which ultimately dictates the sex‐dependent patterns of expression of these CYPs and certain other drug‐metabolizing enzymes. In male rats, the intermittent, pulsatile pattern of GH secretion stimulates the expression of male‐specific liver enzymes, whereas the more continuous pattern of GH release in females suppresses the expression male‐specific enzymes while inducing female‐specific enzymes. The current view is that the transcription factors STAT5b and HNF4α coordinately regulate the action of GH and its resultant effect on the sex‐dependent expression of hepatic CYP genes and thus provide a molecular basis for sex differences in drug metabolism.

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Inadequacy of the Janus Kinase 2/Signal Transducer and Activator of Transcription Signal Transduction Pathway to Mediate Episodic Growth Hormone-Dependent Regulation of Hepatic CYP2C11

Cited by 27 publications

References 34 publications

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

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

Attenuated Expression of Episodic Growth Hormone-Induced CYP2C11 in Female Rats Associated with Suboptimal Activation of the Jak2/Stat5B and Other Modulating Signaling Pathways

Sex Differences in Drug Metabolism

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