Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
Biochem Pharmacol. 2015 Jan 1;93(1):92-103. doi: 10.1016/j.bcp.2014.10.010. Epub 2014 Oct 31.
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.
许多药物的药理学特征存在性别差异，部分原因是女性中 CYP3A4 的表达占主导地位，CYP3A4 是负责药物代谢的最重要的 CYP 同工酶。转录因子在对性别依赖性生长激素 (GH) 分泌的反应中触发药物代谢酶的性别二态性表达。我们使用 HepG2 细胞、生长激素受体 (GHR) 敲除小鼠以及去势和垂体切除术大鼠模型，研究了 HNF6、C/EBPα 和 RXRα 在调节人类女性主导的 CYP3A4、小鼠女性特异性 CYP3A41 和大鼠男性特异性 CYP3A2 表达中的作用，这些表达受 GH 分泌模式的影响。HNF6 和 RXRα 的组成型表达依赖于 GH，GHR 缺乏会降低 HNF6/C/EBPα 复合物水平并增加 HNF6/RXRα 复合物水平。女性 GH 分泌诱导 HNF6 和 C/EBPα 与 CYP3A4 和 Cyp3a41 启动子结合，并且与男性模式相比，HNF6/C/EBPα 复合物水平的结合效率更高。此外，通过女性 GH 分泌观察到对 RXRα 与 CYP3A4 和 Cyp3a41 启动子结合的更大抑制作用，并且观察到的 HNF6/RXRα 复合物水平的抑制作用也较小，而通过男性模式则观察到较小的抑制作用。HNF6、C/EBPα 和 RXRα 与 CYP3A2 启动子的结合不受雄激素直接调节。RXRα 完全消除了 HNF6 和 C/EBPα 对 CYP3A4、Cyp3a41 和 CYP3A2 启动子的协同激活作用。结果表明，性别依赖性 GH 分泌模式会影响 HNF6、C/EBPα 和 RXRα 的表达和相互作用及其与 CYP3A 基因的结合。RXRα 作为一种重要的信号分子，介导 GH 对 CYP3A 表达的性别依赖性影响。
