title: Protective role of hydroxysteroid sulfotransferase in lithocholic acid-induced liver toxicity.
abstract: 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 3alpha-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 6beta-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.
authors.affiliation: Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kitada
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyata
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Aki
authors.initials: A
authors.lastname: Tozawa
authors.forename: Wataru
authors.initials: W
authors.lastname: Honma
authors.forename: Miki
authors.initials: M
authors.lastname: Shimada
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nagata
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sinal
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport; D015152:Blotting, Northern; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D000072469:Cytochrome P450 Family 3; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D007700:Kinetics; D008095:Lithocholic Acid / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases / Q000378:metabolism; D015238:Sulfotransferases / Q000494:pharmacology*; D013658:Taurolithocholic Acid / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D001647:Bile Acids and Salts; D000072469:Cytochrome P450 Family 3; D004268:DNA-Binding Proteins; D008095:Lithocholic Acid; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases; D015238:Sulfotransferases; D013658:Taurolithocholic Acid; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C071543:cytochrome P450 CYP3A10 (hamster); C028152:alcohol sulfotransferase