Retinoid X receptor α regulates the expression of glutathione S-transferase genes and modulates acetaminophen-glutathione conjugation in mouse liver
Retinoid X receptor α regulates the expression of glutathione S-transferase genes and modulates acetaminophen-glutathione conjugation in mouse liver
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DOI：
10.1124/mol.105.013680
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发表时间：
2005-12-01
影响因子：
3.6
通讯作者：
Wan, YJY
中科院分区：
文献类型：
--
作者：
Dai, GL;Chou, N;Wan, YJY
核受体包括构成雄烷受体、孕烷X受体和维甲酸X受体(RXR)，通过调节细胞色素P450(P450)相基因的表达来调节对乙酰氨基酚(APAP)诱导的肝毒性。然而，它们是否在第二阶段水平上调节APAP脱毒还没有完全解决。本研究的目的是评估RXRα在APAP酶介导的II期解毒中的作用。野生型和肝细胞特异性RXRα基因敲除小鼠接受中毒剂量的APAP(500 mg/kg ip)治疗。尽管突变小鼠的基础肝脏谷胱甘肽(GSH)水平显著低于野生型小鼠，但突变小鼠仍可免受APAP诱导的肝毒性。APAP代谢产物的高效液相色谱分析显示，与野生型小鼠相比，突变小鼠肝脏和胆汁中APAP-GSH结合物的水平显著增加。此外，肝细胞RXRα缺乏改变了谷胱甘肽S转移酶(GST)家族的基因表达谱。在肝细胞特异性RXRα缺陷小鼠中，所研究的15个GST基因中有13个的基础表达发生了变化。这可能导致APAP-GSH结合增强和N-乙酰-对苯二酚亚胺的积累减少，N-乙酰-对苯二酚亚胺是一种有毒的电泳体，由I相P450酶对APAP进行生物转化而产生。总之，本研究提供的数据定义了控制APAP-GSH结合的RXRα-GST调控网络。这份报告揭示了一种潜在的新策略，通过RXRα介导的途径操纵GST活性来增强APAP或其他外源生物的解毒作用。
Nuclear receptors, including constitutive androstane receptor, pregnane X receptor, and retinoid X receptor (RXR), modulate acetaminophen(APAP)-induced hepatotoxicity by regulating the expression of phase I cytochrome P450 ( P450) genes. It has not been fully resolved, however, whether they regulate APAP detoxification at the phase II level. The aim of the current study was to evaluate the role of RXR alpha in phase II enzyme-mediated detoxification of APAP. Wild-type and hepatocyte-specific RXR alpha knockout mice were treated with a toxic dose of APAP ( 500 mg/ kg i.p.). Mutant mice were protected from APAP-induced hepatotoxicity, even though basal liver glutathione (GSH) levels were significantly lower in mutant mice compared with those of wild-type mice. High-performance liquid chromatography analysis of APAP metabolites revealed significantly greater levels of APAP-GSH conjugates in livers and bile of mutant mice compared with those of wild-type mice. Furthermore, hepatocyte RXR alpha deficiency altered the gene expression profile of the glutathione S-transferase (Gst) family. Basal expression of 13 of 15 Gst genes studied was altered in hepatocyte-specific RXR alpha-deficient mice. This probably led to enhanced APAP-GSH conjugation and reduced accumulation of N-acetyl-p-benzoquinone imine, a toxic electrophile that is produced by biotransformation of APAP by phase I P450 enzymes. In conclusion, the data presented in this study define an RXR alpha-Gst regulatory network that controls APAP-GSH conjugation. This report reveals a potential novel strategy to enhance the detoxification of APAP or other xenobiotics by manipulating Gst activity through RXR alpha-mediated pathways.