Sex-dependent regulation of hepatic CYP3A by growth hormone: Roles of HNF6, C/EBPα, and RXRα
Sex-dependent regulation of hepatic CYP3A by growth hormone: Roles of HNF6, C/EBPα, and RXRα
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DOI：
10.1016/j.bcp.2014.10.010
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发表时间：
2015-01-01
影响因子：
5.8
通讯作者：
Yue, Jiang
中科院分区：
文献类型：
--
作者：
Li, Jie;Wan, Yu;Yue, Jiang
许多药物药理学特征的性别差异部分是由于CYP 3A 4的女性主导表达，CYP 3A 4是负责药物代谢的最重要的CYP 3A 4亚型。转录因子触发药物代谢酶的性别二态表达，以响应性别依赖性生长激素（GH）分泌。我们使用HepG 2细胞、生长激素受体（GHR）敲除小鼠以及睾丸切除术和垂体切除术的大鼠模型，通过GH分泌模式研究了HNF 6、C/EBP α和RXR α在调节人类女性主导型CYP 3A 4、小鼠女性特异性CYP 3A 41和大鼠男性特异性CYP 3A 2表达中的作用。HNF 6和RXR α的组成型表达。GH依赖性，GHR缺乏降低HNF 6/C/EBP α复合物水平，增加HNF 6/RXR α复合物水平。女性GH分泌诱导HNF 6和C/EBP α与CYP 3A 4和Cyp 3a 41启动子结合，且HNF 6/C/EBP α复合物水平比男性更有效。此外，女性GH分泌对RXR α与CYP 3A 4和Cyp 3a 41启动子的结合以及HNF 6/RXR α复合物水平的抑制作用更大，但男性GH分泌对RXR α的抑制作用较小。HNF 6、C/EBP α和RXR α与CYP 3A 2启动子的结合不受雄激素的直接调节。RXR α完全消除了HNF 6和C/EBP α对CYP 3A 4、Cyp 3a 41和CYP 3A 2启动子的协同激活作用。结果表明，性别依赖性GH分泌模式影响HNF 6、C/EBP α和RXR α的表达和相互作用，以及它们与CYP 3A基因的结合。RXR α介导GH对CYP 3A表达的性别依赖性影响，是一种重要的信号分子。(C)2014爱思唯尔公司All rights reserved.
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/EBP alpha, and RXR alpha 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 RXR alpha. was GH-dependent, and GHR deficiency decreased HNF6/C/EBP alpha complex levels and increased HNF6/RXR alpha complex levels. Feminine GH secretion induced the binding of HNF6 and C/EBP alpha to the CYP3A4 and Cyp3a41 promoters and HNF6/C/EBP alpha complex levels was more efficiently compared with masculine pattern. Additionally, a greater inhibition of the binding of RXR alpha to the CYP3A4 and Cyp3a41 promoters and HNF6/RXR alpha complex levels was observed by feminine GH secretion, but less inhibition was observed by masculine pattern. The binding of HNF6, C/EBP alpha, and RXR alpha to the CYP3A2 promoter was not directly regulated by androgens. RXR alpha completely abolished the synergistic activation of the CYP3A4, Cyp3a41, and CYP3A2 promoters by HNF6 and C/EBP alpha. The results demonstrate that sex-dependent GH secretion patterns affect the expressions and interactions of HNF6, C/EBP alpha, and RXR alpha as well as their binding to CYP3A genes. RXR alpha mediates the sex-dependent influence of GH on CYP3A expression as an important signalling molecule. (C) 2014 Elsevier Inc. All rights reserved.