Gender Differences in the Hepatotoxicity and Toxicokinetics of Emodin: The Potential Mechanisms Mediated by UGT2B7 and MRP2

• DOI: 10.1021/acs.molpharmaceut.8b00387
• Publication Date: 2018-07-16T17:48:45Z
• Authors: Lili Wu; Weichao Han; Yulian Chen; Tao Zhang; Junjin Liu; Shilong Zhong; Han Liu; Congcong Han; Zhongyi Zhang; Shuwen Liu; Lan Tang
• Keywords: UGT2B7; Pregnane X receptor; Hepatoblastoma

Emodin is a main anthraquinone compound which exists in Chinese traditional medicines including Polygonum multiflorum and Rhubarb. It documented to have obvious liver kidney toxicity. This study aims (a) estimate gender differences of the hepatotoxicity toxicokinetics rats after oral administration emodin (60 150 mg/kg/d) for consecutive 28 days (b) clarify relative mechanisms caused by glucuronidation disposition. Hepatotoxicity was significantly higher female than that male rats, as evidenced histopathological biochemical tests. Similarly, toxicokinetic profiles time differences, could cause hepatotoxicity. The metabolic transcriptomics data 55 human 36 samples demonstrated UDP-glucuronosyltransferase 2B7 (UGT2B7) predominant enzyme glucuronidation. A genome-wide association (GWAS) identified rs11726899 located within ∼50 kb transcript UGT2B affect metabolism. Knockdown UGT2B7 HepG2 cells decreased increased cytotoxicity emodin. gene expression protein levels were decreased, but those multidrug-resistant-protein 2 (MRP2) being treated with 50 μM 48 h. Long-term use decrease intrinsic clearance (CLint, 18.5%–35.4%) values zidovidue (UGT2B7 substrate) glucuronide both microsomes from administrated days, thus causing accumulation However, self-induced MRP2 lower observed emodin-treated compared rats. Therefore, are potentially mediated coupling vivo.