Anakk Sayeepriyadarshini, Huang Wendong, Staudinger Jeffrey L, Tan Kheng, Cole Timothy J, Moore David D, Strobel Henry W
Department of Biochemistry and Molecular Biology, University of Texas Medical School of Houston, P.O. Box 20708, Houston, TX 77225, USA.
Drug Metab Dispos. 2007 Jan;35(1):36-42. doi: 10.1124/dmd.106.011270. Epub 2006 Oct 4.
The CYP3As are broad-spectrum drug-metabolizing enzymes that are collectively responsible for more than 50% of xenobiotic metabolism. Unlike other CYP3As, murine CYP3A44 is expressed predominantly in the female liver, with much lower levels in male livers and no detectable expression in brain or kidney in either gender. In this study, we examined the role of nuclear hormone receptors in the regulation of Cyp3a44 gene expression. Interestingly, we observed differential effects of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) -mediated activation of Cyp3a44 gene expression, which was gender-specific. For example, activation of PXR by pregnenolone-16alpha-carbonitrile (PCN) and dexamethasone (DEX) induced CYP3A44 mRNA levels in a PXR-dependent fashion in male mice, whereas no induction was detected in female mice. In contrast, PCN and DEX down-regulated CYP3A44 expression in female PXR null animals. Similar to PXR, CAR activation also showed a male-specific induction with no effect on CYP3A44 levels in females. When PXR knockout mice were challenged with the CAR activator phenobarbital, a significant up-regulation of male CYP3A44 levels was observed, whereas levels in females remained unchanged. We conclude that gender has a critical impact on PXR- and CAR-mediated effects of CYP3A44 expression.
细胞色素P450 3A（CYP3A）是一类广谱药物代谢酶，共同负责超过50%的外源性物质代谢。与其他CYP3A不同，小鼠CYP3A44主要在雌性肝脏中表达，在雄性肝脏中的表达水平低得多，且在两性的脑或肾中均未检测到表达。在本研究中，我们研究了核激素受体在Cyp3a44基因表达调控中的作用。有趣的是，我们观察到孕烷X受体（PXR）和组成型雄甾烷受体（CAR）介导的Cyp3a44基因表达激活存在差异效应，且具有性别特异性。例如，孕烯醇酮-16α-腈（PCN）和地塞米松（DEX）激活PXR以PXR依赖的方式诱导雄性小鼠CYP3A44 mRNA水平，而在雌性小鼠中未检测到诱导作用。相反，PCN和DEX下调雌性PXR基因敲除动物中的CYP3A44表达。与PXR类似，CAR激活也显示出雄性特异性诱导，对雌性CYP3A44水平无影响。当用CAR激活剂苯巴比妥对PXR基因敲除小鼠进行刺激时，观察到雄性CYP3A44水平显著上调，而雌性水平保持不变。我们得出结论，性别对PXR和CAR介导的CYP3A44表达效应具有关键影响。
