Gender Differences in the Hepatotoxicity and Toxicokinetics of Emodin: The Potential Mechanisms Mediated by UGT2B7 and MRP2
Gender Differences in the Hepatotoxicity and Toxicokinetics of Emodin: The Potential Mechanisms Mediated by UGT2B7 and MRP2
复制标题
大黄素肝毒性和毒代动力学的性别差异：UGT2B7和MRP2介导的潜在机制
DOI：
10.1021/acs.molpharmaceut.8b00387
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发表时间：
2018
影响因子：
4.9
通讯作者：
Tang Lan
中科院分区：
文献类型：
--
作者：
Wu Lili;Han Weichao;Chen Yulian;Zhang Tao;Liu Junjin;Zhong Shilong;Liu Han;Han Congcong;Zhang Zhongyi;Liu Shuwen;Tang Lan
大黄素是何首乌、大黄等中药中主要的蒽醌类化合物。据记载，其具有明显的肝、肾毒性。本研究旨在（a）评估大鼠连续28天口服大黄素（60和150 mg/kg/d）后肝毒性和毒代动力学的性别差异，以及（b）阐明葡萄糖醛酸化和处置引起的相关机制。组织病理学和生化测试表明，雌性大鼠的肝毒性显着高于雄性大鼠。同样，大黄素的毒代动力学特征也存在时间和性别差异，这可能导致肝毒性的时间和性别差异。 55 个人类肝脏和 36 个人类肾脏样本的代谢和转录组学数据表明，UDP-葡萄糖醛酸基转移酶 2B7 (UGT2B7) 是大黄素葡萄糖醛酸化的主要酶。一项全基因组关联研究 (GWAS) 发现，位于 UGT2B 转录本约 50 kb 范围内的 rs11726899 可以显着影响大黄素代谢。 HepG2细胞中UGT2B7的敲低显着降低了大黄素葡萄糖醛酸化并增加了大黄素的细胞毒性。 50 μM大黄素作用48 h后，HepG2细胞中UGT2B7基因表达量和蛋白水平降低，而多重耐药蛋白2（MRP2）基因表达量和蛋白水平升高。长期使用大黄素可降低给予大黄素28 d的雄性和雌性大鼠肝微粒体中齐多维杜（UGT2B7底物）葡萄糖苷酸的内在清除率（CLint，降低18.5%~35.4%）值，从而导致大黄素蓄积。然而，与雌性大鼠相比，经大黄素处理的雄性大鼠观察到较高的自诱导 MRP2 表达和较低的肝毒性。因此，大黄素肝毒性和毒代动力学的性别差异可能是由体内UGT2B7和MRP2的偶联介导的。
Emodin is a main anthraquinone compound which exists in Chinese traditional medicines includingPolygonum multiflorumandRhubarb. It is documented to have obvious liver and kidney toxicity. This study aims to (a) estimate gender differences of the hepatotoxicity and toxicokinetics in rats after oral administration of emodin (60 and 150 mg/kg/d) for a consecutive 28 days and (b) clarify relative mechanisms caused by glucuronidation and disposition. Hepatotoxicity was significantly higher in female rats than that in male rats, as evidenced by histopathological and biochemical tests. Similarly, the toxicokinetic profiles of emodin have time and gender differences, which could cause time and gender differences in hepatotoxicity. The metabolic and transcriptomics data of 55 human liver and 36 human kidney samples demonstrated that UDP-glucuronosyltransferase 2B7 (UGT2B7) was the predominant enzyme for emodin glucuronidation. A genome-wide association study (GWAS) identified that rs11726899 located within ∼50 kb of the transcript of UGT2B could significantly affect emodin metabolism. Knockdown of UGT2B7 in HepG2 cells significantly decreased emodin glucuronidation and increased cytotoxicity of emodin. The gene expression and protein levels of UGT2B7 were decreased, but those of the multidrug-resistant-protein 2 (MRP2) were increased in HepG2 cells after being treated with 50 μM emodin for 48 h. Long-term use of emodin could decrease the intrinsic clearance (CLint, decreased by 18.5%–35.4%) values of zidovidue (UGT2B7 substrate) glucuronide in both male and female liver microsomes from rats administrated with emodin for 28 days, thus causing the accumulation of emodin. However, higher self-induced MRP2 expression and lower hepatotoxicity were observed in emodin-treated male rats compared to that in female rats. Therefore, gender differences in the hepatotoxicity and toxicokinetics of emodin are potentially mediated by the coupling of UGT2B7 and MRP2 in vivo.