title: The role of Ntcp, Oatp2, Bsep and Mrp2 in liver injury induced by Dioscorea bulbifera L. and Diosbulbin B in mice.
abstract: Dioscorea bulbifera L. (DB) is a traditional Chinese herb used in thyroid disease and cancer. However, the clinical use of DB remains a challenge due to its hepatotoxicity, which is caused, in part, by the presence of Diosbulbin B (DIOB), a toxin commonly found in DB extracts. As abnormal expression of hepatobiliary transporters plays an important role in drug-induced liver injury, we assessed the hepatotoxicity induced by DB and DIOB, and explored their impacts on hepatobiliary transporter expression levels. Following liquid chromatography-tandem mass analysis of the DIOB content of DB extract, male ICR mice were randomly orally administered DB or DIOB for 14days. Liver injury was assessed by histopathological and biochemical analysis of liver fuction. The levels of transporter protein and mRNA were determined by western blotting and real-time PCR. Liver function and histopathological analysis indicated that both DB and DIOB could induce liver injury in mice, and that DIOB might be the primary toxic compound in DB. Moreover, down-regulation of Mrp2 blocked the excretion of bilirubin, glutathione disulfide, and bile acids, leading to the accumulation of toxic substrates in the liver and a redox imbalance. We identified down-regulated expression of Mrp2 as potential factors linked to increased serum bilirubin levels and decreased levels of glutathione in the liver and increased liver injury severity. In summary, our study indicates that down-regulation of Mrp2 represents the primary mechanism of DB- and DIOB-induced hepatotoxicity, and provides insight into novel therapies that could be used to prevent DB- and DIOB-mediated liver injury.
authors.affiliation: Depatment of Pharmacy, the First Hospital of Jilin University, Changchun, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Qu
authors.affiliation: Depatment of Pharmacy, the First Hospital of Jilin University, Changchun, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Tao
authors.affiliation: Depatment of Pharmacy, the First Hospital of Jilin University, Changchun, China.
authors.forename: Si-Xi
authors.initials: SX
authors.lastname: Zhang
authors.affiliation: Changchun University of Chinese Medicine, Changchun, China.
authors.forename: Jing-Meng
authors.initials: JM
authors.lastname: Sun
authors.affiliation: Department of Hepatology, the First Hospital of Jilin University, Changchun, China.
authors.forename: Jun-Qi
authors.initials: JQ
authors.lastname: Niu
authors.affiliation: Phase I Clinical Trial Unit, the First Hospital of Jilin University, Changchun, China.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Ding
authors.affiliation: Depatment of Pharmacy, the First Hospital of Jilin University, Changchun, China. Electronic address: yanqingyjk@163.com.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Song
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D027742:Dioscorea / Q000737:chemistry*; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000302:isolation & purification / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008813:Mice, Inbred ICR; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004365:Drugs, Chinese Herbal; D006576:Heterocyclic Compounds, 4 or More Rings; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027701:Organic Cation Transport Proteins; D027981:Symporters; C490549:Abcb11 protein, mouse; C464433:Oatp2 protein, mouse; C071908:sodium-bile acid cotransporter; C569454:diosbulbin B
keywords: Bile salt export pump; Diosbulbin B; Dioscorea bulbifera L.; Multidrug resistance associated protein 2; Na+-taurocholate co-transporting polypeptide; Organic anion transporting polypeptide 2