Role for enhanced faecal excretion of bile acid in hydroxysteroid sulfotransferase-mediated protection against lithocholic acid-induced liver toxicity

M. Miyata, H. Watase, W. Hori, M. Shimada, K. Nagata, F. J. Gonzalez, Y. Yamazoe

    Research output: Contribution to journalArticlepeer-review

    20 Citations (Scopus)

    Abstract

    The efficient clearance of toxic bile acids such as lithocholic acid (LCA) requires drug-metabolizing enzymes. We therefore assessed the influence of pregnenolone 16α-carbonitrile (PCN) treatment on LCA-induced hepatotoxicity and disposition of LCA metabolites using female farnesoid X receptor (FXR)-null and wild-type mice. Marked decreases in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, and hepatic tauroLCA (TLCA) concentrations were found in LCA-fed wild-type mice co-treated with PCN. Whereas induction of Cyp3a and hydroxysteroid sulfotransferase (Sult2a) proteins was observed in FXR-null and wild-type mice, clear increases in biliary 3α-sulfated TLCA but not total 6α-hydroxy LCA (taurohyodeoxycholic acid and hyodeoxycholic acid) were only observed in PCN-treated wild-type mice. Biliary 3α-sulfated TLCA output rate was increased 7.2-fold, but accounts for only 4.2% of total bile acid output rate in LCA and PCN-co-treated wild-type mice. Total 3α-sulfated LCA (LCA and TLCA) was, however, the most abundant bile acid component in faeces suggesting that efficient faecal excretion of biliary 3α-sulfated TLCA through escape from enterohepatic circulation. FXR-null mice, which have constitutively high levels of the Sult2a protein, were fed a diet supplemented with 1% LCA and 0.4% dehydroepiandrosterone (DHEA), a typical Sult2a substrate/inhibitor. The faecal total 3α-sulfated bile acid excretion was reduced to 62% of FXR-null mice fed only the LCA diet. Hepatic TLCA concentration and serum AST activity were significantly higher in FXR-null mice fed DHEA and LCA diet than in FXR-null mice fed the LCA diet or DHEA diet. These results suggest that hepatic formation of 3α-sulfated TLCA is a crucial factor for protection against LCA-induced hepatotoxicity.

    Original languageEnglish
    Pages (from-to)631-644
    Number of pages14
    JournalXenobiotica
    Volume36
    Issue number7
    DOIs
    Publication statusPublished - 2006 Jul 1

    Keywords

    • Farnesoid X receptor (FXR)
    • Hydroxysteroid sulfotransferase (Sult2a)
    • Lithocholic acid
    • Pregnenolone 16α-carbonitrile (PCN)
    • Sulfation
    • Toxicity

    ASJC Scopus subject areas

    • Biochemistry
    • Toxicology
    • Pharmacology
    • Health, Toxicology and Mutagenesis

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