Attenuated expression of episodic growth hormone-induced CYP2C11 in female rats associated with suboptimal activation of the Jak2/Stat5B and other modulating signaling pathways.
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-kappaB in the episodic GH-treated females that may be involved in attenuating the activity of the Jak2/Stat5B pathway diminishing CYP2C11 expression levels.
Dhir
Ravindra N
RN
Laboratories of Biochemistry, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce St., Philadelphia, PA 19104-6048, USA.
Thangavel
Chellappagounder
C
Shapiro
Bernard H
BH
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D013006:Growth Hormone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007016:Hypophysectomy; D020672:I-kappa B Proteins / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects*; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism
D020672:I-kappa B Proteins; D008565:Membrane Proteins; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D050799:STAT5 Transcription Factor; C494094:Stat5a protein, rat; C494097:Stat5b protein, rat; D000072000:NF-KappaB Inhibitor alpha; D013006:Growth Hormone; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C456179:Cyp2a1 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases