Calculus Bovis Sativus up-regulates hepatic protein 2(Mrp2) and Mrp4 in 17α-ethynylestradiol-induced cholestasis via a regulatory effect on ER signaling  

作　　者：Wu Tao Liu Dong Song Hongping 

机构地区：[1]Department of Pharmacy, Wuhan Fourth Hospital/Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [2]Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China

出　　处：《Journal of Traditional Chinese Medicine》2019年第3期402-409,共8页中医杂志（英文版）

基　　金：Supported by the National Natural Science Foundation of China(Study of the Role and Mechanism of PDZK1 Protein in the Downregulation of Mrp2 by Estrogen in Cholestasis,No.81503146 and Study of the Choleretic Effect of Calculus Bovis Sativus Based on PDZK1 Protein Interaction Networks and Bile Acid Metabolic Profile,No.81573788);Science Foundations of Health and Family Planning Commission of Wuhan Municipality(No.WZ15Z02)

摘　　要：OBJECTIVE:To investigate the pathway through which Calculus Bovis Sativus (CBS) up-regulates hepatic multidrug resistance-associated protein 2 (Mrp2) and Mrp4 in 17α-ethynylestradiol (EE)-induced cholestasis.METHODS:Five groups of rats were designed:control group,EE+ICI182780 group,EE group,EE+CBS 50 mg/kg group and EE + CBS 150 mg/kg group.CBS (50 and 150 mg.kg-1· d-1) was orally given to rats by gavage for five consecutive days in coadministration with EE.The levels of cholestasis biomarkers,alanine aminotransferase (ALT),aspartate aminotransferase (AST),alkaline phosphatase (ALP) and total bilirubin (TBIL) were determined by biochemical methods.The bile flow was measured.The histopathology of the liver tissue was evaluated.The expression of Mrp2,Mrp3,Mrp4,estrogen receptor α(ERα) and ERβ was determined by Western blotting.RESULTS:CBS markedly improved EE-induced cholestasis.EE exposure significantly reduced hepatic Mrp2 and Mrp4 expression compared with the control group.EE also dramatically up-regulated the expression of Mrp3.Compared to the EE group,CBS notably up-regulated hepatic Mrp2 and Mrp4 but failed to influence the Mrp3 level significantly.ICI182780,an ER antagonist,showed similar beneficial effects as CBS.Decreased expression of Mrp2 and Mrp4 caused by EE was also restored by IC1182780.Additionally,EE significantly induced hepatic ERα expression,which was reversed by ICI182780 or CBS (150 mg/kg) treatment,suggesting that CB5 exerted a moderate regulatory effect on ER signaling.CONCLUSION:CBS up-regulated hepatic Mrp2 and Mrp4 expression in EE-induced cholestasis,which might be associated with its regulation of ER signaling.OBJECTIVE:To investigate the pathway through which Calculus Bovis Sativus（CBS）up-regulates hepatic multidrug resistance-associated protein 2（Mrp2）and Mrp4 in 17 a-ethynylestradiol（EE）-induced cholestasis.METHODS:Five groups of rats were designed:control group,EE+ICI182780 group,EE group,EE+CBS50 mg/kg group and EE+CBS 150 mg/kg group.CBS(50 and 150 mg·kg-1·d-1) was orally given to rats by gavage for five consecutive days in coadministration with EE.The levels of cholestasis biomarkers,alanine aminotransferase（ALT）,aspartate aminotransferase（AST）,alkaline phosphatase（ALP）and total bilirubin（TBIL）were determined by biochemical methods.The bile flow was measured,The histopathology of the liver tissue was evaluated.The expression of Mrp2,Mrp3,Mrp4,estrogen receptor α（ERα）and ERB was determined by Western blotting.RESULTS:CBS markedly improved EE-induced cholestasis.EE exposure significantly reduced hepatic Mrp2 and Mrp4 expression compa red with the control group.EE also dramatically up-regulated the expression of Mrp3.Compared to the EE group,CBS notably up-regulated hepatic Mrp2 and Mrp4 but failed to influence the Mrp3 level significantly.ICI1 82780,an ER antagonist,showed similar beneficial effects as CBS.Decreased expression of Mrp2 and Mrp4 caused by EE was also restored by ICI1 82780.Additionally,EE significantly induced hepatic ERa expression,which was reversed by ICI1 82780 or CBS（1 50 mg/kg）treatment,suggesting that CBS exerted a moderate regulatory effect on ER signaling.CONCLUSION:CBS up-regulated hepatic Mrp2 and Mrp4 expression in EE-induced cholestasis,which might be associated with its regulation of ER signaling.

关 键 词：Calculus BOVIS ETHYNYLESTRADIOL Receptors estrogen MULTIDRUG resistance-associated proteins ICI182780 

分 类 号：R285.5[医药卫生—中药学]