Dioscin protects against ANIT-induced cholestasis via regulating Oatps, Mrp2 and Bsep expression in rats.
Alpha-naphthylisothiocyanate (ANIT) is a toxicant that is widely used in rodents to model human intrahepatic cholestasis. The aim of the study is to investigate whether effects of dioscin on ANIT-induced cholestasis are related to changes in expression of hepatic transporters in rats. Effects of dioscin on cholestasis were examined by histology and biochemical marker levels. The functional changes of hepatic transporters were determined by in vitro, in situ and in vivo. qRT-PCR and western blot were used to assess the expression of hepatic transporters in cholestatic rats. Dioscin administration could ameliorate cholestasis, as evidenced by reduced biochemical markers as well as improved liver pathology. The uptakes of organic anion transporting polypeptide (Oatp) substrates were altered in liver uptake index in vivo, perfused rat liver in situ and isolated rat hepatocytes in vitro in cholestasis rats. qRT-PCR and western blot analysis indicated co-treatment of ANIT with dioscin prevented the adaptive down-regulation of Oatp1a1, 1b2, and prompted the up-regulation of Oatp1a4, multidrug resistance-associated protein (Mrp) 2 and bile salt export pump (Bsep). In addition, concerted effects on Mrp2 and Bsep occurred through up-regulation of small heterodimer partner by activating farnesoid X receptor. Dioscin might prevent impairment of hepatic function by restoring hepatic transporter expression.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China. Electronic address: zhangaijie1986@163.com.
Aijie
A
Zhang
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China. Electronic address: yongmingjiahlj@126.com.
Yongming
Y
Jia
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China. Electronic address: xulianglinyao@126.com.
Qinghan
Q
Xu
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China. Electronic address: wangcyuan@163.com.
Changyuan
C
Wang
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China. Electronic address: llaqii@yahoo.com.cn.
Qi
Q
Liu
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China. Electronic address: mengq531@yahoo.cn.
Qiang
Q
Meng
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China. Electronic address: jinyongpeng2005@163.com.
Jinyong
J
Peng
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China. Electronic address: sunhuijun@hotmail.com.
Huijun
H
Sun
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China. Electronic address: spfar1004@gmail.com.
Pengyuan
P
Sun
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China. Electronic address: huoxiaokui@163.com.
Xiaokui
X
Huo
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China. Electronic address: kexinliu@dlmedu.edu.cn.
Kexin
K
Liu
D015058:1-Naphthylisothiocyanate; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004970:Estrone / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D020011:Protective Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D015058:1-Naphthylisothiocyanate; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004144:Diosgenin; D004970:Estrone; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; D020011:Protective Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C000715087:ABCC2 protein, human; C490548:Abcb11 protein, rat; C423013:Abcc2 protein, rat; C019357:dioscin; C017296:estrone sulfate
ANIT-induced cholestasis; Bsep; Dioscin; Mrp2; Oatps