title: ME3738 protects against lithocholic acid-induced hepatotoxicity, which is associated with enhancement of biliary bile acid and cholesterol output.
abstract: ME3738 (22beta-methoxyolean-12-ene-3beta, 24(4beta)-diol), a derivative of soyasapogenol, attenuates liver disease in several models of chronic liver inflammation. In the present study, we have investigated a protective effect of ME3738 in a typical bile acid-induced cholestatic liver model, lithocholate (LCA) feeding mouse. Co-administration of ME3738 resulted in decreases in plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities and hepatic bile acid level, and increases in biliary outputs of bile acid and cholesterol, as compared with the results in mice treated with LCA alone. LCA sulfation by hydroxysteroid sulfotransferase 2a and hydroxylation have been reported to be involved in protection against LCA-induced hepatotoxicity. ME3738-treatment, however, had no clear influence on the hydroxysteroid sulfotransferase 2a protein level and LCA 6alpha-, 6beta- and 7alpha-hydroxylase activities, but increased biliary cholesterol output. Cholate (CA)-treatment has been shown to induce hepatotoxicity in farnesoid X receptor-null mice, which is scarcely dependent on bile acid sulfation and hydroxylation but associated with decreased biliary bile acid output. Co-administration of ME3738 decreased the ALT and ALP activities and hepatic bile acid level, and increased biliary outputs of bile acid and cholesterol in farnesoid X receptor-null mice, as compared with the results in the mice treated with CA. Moreover, a clear correlation between biliary outputs of cholesterol and bile acid was observed in these two bile acid-induced hepatotoxicity mouse models. These results suggest that ME3738 protects against bile acid-induced hepatotoxicity through increased biliary bile acid output that is not related to bile acid metabolism but associated with cholesterol output.
authors.affiliation: Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nomoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyata
authors.forename: Miki
authors.initials: M
authors.lastname: Shimada
authors.forename: Kouichi
authors.initials: K
authors.lastname: Yoshinari
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shibasaki
authors.forename: Tohru
authors.initials: T
authors.lastname: Kurosawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shindo
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000032:analysis; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000032:analysis / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D008095:Lithocholic Acid / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D015238:Sulfotransferases / Q000032:analysis
chemical_list: D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; C477463:ME3738; D012333:RNA, Messenger; D008095:Lithocholic Acid; D009828:Oleanolic Acid; D002784:Cholesterol; D015238:Sulfotransferases; C028152:alcohol sulfotransferase