Emodin is a main anthraquinone compound which exists in Chinese traditional medicines including Polygonum multiflorum and Rhubarb. 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 (CL_int, 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.

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大黄素在肝毒性和毒代动力学方面的性别差异：UGT2B7和MRP2介导的潜在机制

大黄素是一种主要的蒽醌化合物，存在于何首乌和大黄中。。据证明具有明显的肝肾毒性。这项研究旨在（a）估计连续28天口服大黄素（60和150 mg / kg / d）后连续28天大鼠肝毒性和毒代动力学的性别差异，以及（b）阐明由葡萄糖醛酸苷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曲线具有时间和性别差异，这可能导致肝毒性的时间和性别差异。55个人类肝脏和36个人类肾脏样品的代谢和转录组学数据表明，UDP-葡萄糖醛酸转移酶2B7（UGT2B7）是大黄素葡萄糖醛酸化的主要酶。全基因组关联研究（GWAS）发现，位于UGT2B转录物约50 kb内的rs11726899可以显着影响大黄素的代谢。在HepG2细胞中敲除UGT2B7可显着降低大黄素的葡萄糖醛酸化作用，并增加大黄素的细胞毒性。用50μM大黄素处理48h后，HepG2细胞中UGT2B7的基因表达和蛋白水平降低，但多药耐药蛋白2（MRP2）的基因表达和蛋白水平升高。长期使用大黄素可能会降低内在清除率（CL 但用50μM大黄素处理48 h后，HepG2细胞中的多药耐药蛋白2（MRP2）的表达增加。长期使用大黄素可能会降低内在清除率（CL 但用50μM大黄素处理48 h后，HepG2细胞中的多药耐药蛋白2（MRP2）的表达增加。长期使用大黄素可能会降低内在清除率（CL_int，用大黄素注射28天的大鼠的雌性和雄性肝微粒体中，齐多维德（UGT2B7底物）葡糖醛酸苷的值降低了18.5％–35.4％），从而导致了大黄素的积累。然而，在大黄素处理过的雄性大鼠中，与雌性大鼠相比，观察到较高的自我诱导的MRP2表达和较低的肝毒性。因此，大黄素在肝毒性和毒代动力学方面的性别差异可能是通过体内UGT2B7和MRP2的偶联介导的。