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Sex-dependent regulation of hepatic CYP3A by growth hormone: Roles of HNF6, C/EBPα, and RXRα.
Biochem Pharmacol
January 2015
Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China. Electronic address:
Sex-based differences in the pharmacological profiles of many drugs are due in part to the female-predominant expression of CYP3A4, which is the most important CYP isoform responsible for drug metabolism. Transcription factors trigger the sexually dimorphic expression of drug-metabolizing enzymes in response to sex-dependent growth hormone (GH) secretion. We investigated the roles of HNF6, C/EBPα, and RXRα in the regulation of human female-predominant CYP3A4, mouse female-specific CYP3A41, and rat male-specific CYP3A2 expression by GH secretion patterns using HepG2 cells, growth hormone receptor (GHR) knockout mice as well as rat models of orchiectomy and hypophysectomy.
View Article and Find Full Text PDFSex-dependent expression of CYP2C11 in spleen, thymus and bone marrow regulated by growth hormone.
Biochem Pharmacol
November 2007
Laboratories of Biochemistry, Univeristy of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6048, USA.
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.
View Article and Find Full Text PDFAttenuated expression of episodic growth hormone-induced CYP2C11 in female rats associated with suboptimal activation of the Jak2/Stat5B and other modulating signaling pathways.
Drug Metab Dispos
November 2007
Laboratories of Biochemistry, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce St., Philadelphia, PA 19104-6048, USA.
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.
View Article and Find Full Text PDFA molecular basis for the sexually dimorphic response to growth hormone.
Endocrinology
June 2007
Laboratories of Biochemistry, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6048, USA.
Once reserved solely for the treatment of short stature, the now readily available recombinant GH has expanded the use of the hormone to include the treatment of cardiovascular, renal, muscular, skeletal, immunological, psychosocial, and metabolic abnormalities associated with GH deficiency. There are also proposals for the widespread use of the hormone to ameliorate or reverse aging. However, this extensive use of GH has revealed intrinsic sexual dimorphisms in which females are considerably less responsive to the therapeutic regimen than are males.
View Article and Find Full Text PDF[Amenorrhea-galactorrhea syndrome].
Nihon Rinsho
June 2006
Division of Obstetrics and Gynecology, Department of Reproductive, Pediatric and Infectious Science, Yamaguchi University School of Medicine.
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