title: Sex-dependent regulation of hepatic CYP3A by growth hormone: Roles of HNF6, C/EBPα, and RXRα.
abstract: 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. The constitutive expression of HNF6 and RXRα was GH-dependent, and GHR deficiency decreased HNF6/C/EBPα complex levels and increased HNF6/RXRα complex levels. Feminine GH secretion induced the binding of HNF6 and C/EBPα to the CYP3A4 and Cyp3a41 promoters and HNF6/C/EBPα complex levels was more efficiently compared with masculine pattern. Additionally, a greater inhibition of the binding of RXRα to the CYP3A4 and Cyp3a41 promoters and HNF6/RXRα complex levels was observed by feminine GH secretion, but less inhibition was observed by masculine pattern. The binding of HNF6, C/EBPα, and RXRα to the CYP3A2 promoter was not directly regulated by androgens. RXRα completely abolished the synergistic activation of the CYP3A4, Cyp3a41, and CYP3A2 promoters by HNF6 and C/EBPα. The results demonstrate that sex-dependent GH secretion patterns affect the expressions and interactions of HNF6, C/EBPα, and RXRα as well as their binding to CYP3A genes. RXRα mediates the sex-dependent influence of GH on CYP3A expression as an important signalling molecule.
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Na
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Xiaochan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Baotou Teachers' College, Inner Mongolia University of Science & Technology, Baotou 014030, China.
authors.forename: Guicheng
authors.initials: G
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Zheqiong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China. Electronic address: yuejiang@whu.edu.cn.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yue
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D056945:Hep G2 Cells; D051559:Hepatocyte Nuclear Factor 6 / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D047490:Retinoid X Receptor alpha / Q000502:physiology*; D012727:Sex Characteristics; D008565:Membrane Proteins
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D013006:Growth Hormone; D051559:Hepatocyte Nuclear Factor 6; D047490:Retinoid X Receptor alpha; C530718:CEBPA protein, mouse; C496606:Onecut1 protein, mouse; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins
keywords: Drug metabolism; Nuclear receptor; Sexually dimorphism; Transcription factor