Protective Role of Hydroxysteroid Sulfotransferase in Lithocholic Acid-induced Liver Toxicity

• Published in: The Journal of biological chemistry Vol. 278; no. 20; pp. 17838 - 17844
• Main Authors: Kitada, Hirotaka, Miyata, Masaaki, Nakamura, Toshifumi, Tozawa, Aki, Honma, Wataru, Shimada, Miki, Nagata, Kiyoshi, Sinal, Christopher J, Guo, Grace L, Gonzalez, Frank J, Yamazoe, Yasushi
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 16.05.2003
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases - metabolism; Bile Acids and Salts - metabolism; Biological Transport; Blotting, Northern; Blotting, Western; Cell Nucleus - metabolism; Cytochrome P450 Family 3; DNA-Binding Proteins - genetics; Dose-Response Relationship, Drug; Female; Kinetics; Lithocholic Acid - toxicity; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Receptors, Cytoplasmic and Nuclear; Steroid Hydroxylases - metabolism; Sulfotransferases - pharmacology; Taurolithocholic Acid - metabolism; Time Factors; Transcription Factors - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M210634200

Supplement of 1% lithocholic acid (LCA) in the diet for 5–9 days resulted in elevated levels of the marker for liver damage aspartate aminotransferase and alkaline phosphatase activities in both farnesoid X receptor (FXR)-null and wild-type female mice. The levels were clearly higher in wild-type mice than in FXR-null mice, despite the diminished expression of a bile salt export pump in the latter. Consistent with liver toxicity marker activities, serum and liver levels of bile acids, particularly LCA and taurolithocholic acid, were clearly higher in wild-type mice than in FXR-null mice after 1% LCA supplement. Marked increases in hepatic sulfating activity for LCA (5.5-fold) and hydroxysteroid sulfotransferase (St) 2a (5.8-fold) were detected in liver of FXR-null mice. A 7.4-fold higher 3α-sulfated bile acid concentration was observed in bile of FXR-null mice fed an LCA diet compared with that of wild-type mice. Liver St2a content was inversely correlated with levels of alkaline phosphatase. In contrast, microsomal LCA 6β-hydroxylation was not increased and was in fact lower in FXR-null mice compared in wild-type mice. Clear decreases in mRNA encoding sodium taurocholate cotransporting polypeptide, organic anion transporting polypeptide 1, and liver-specific organic anion transporter-1 function in bile acid import were detected in LCA-fed mice. These transporter levels are higher in FXR-null mice than wild-type mice after 1% LCA supplement. No obvious changes were detected in the Mrp2, Mrp3, and Mrp4 mRNAs. These results indicate hydroxysteroid sulfotransferase-mediated LCA sulfation as a major pathway for protection against LCA-induced liver damage. Furthermore, Northern blot analysis using FXR-null, pregnane X receptor-null, and FXR-pregnane X receptor double-null mice suggests a repressive role of these nuclear receptors on basal St2a expression.