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.