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Altered integrity and decreased expression of hepatocyte tight junctions in rifampicin-induced cholestasis in mice.

Abstract
Rifampicin is a well-known hepatotoxicant, but little is known about the mechanism of rifampicin-induced hepatotoxicity. The aim of this study was to characterize the expression and localization of hepatocyte tight junctions in rifampicin-induced cholestasis in mice. Cholestasis was induced by administration of rifampicin (200 mg/kg) for 7 consecutive days or treatment with a single dose of rifampicin (200 mg/kg) by gastric intubation. The expression of mRNA for hepatic zonula occludens (ZO)-1, ZO-2, ZO-3, occludin and claudin-1 was determined using RT-PCR. Localization of ZO-1 and occludin was detected using immunofluorescence. Results showed that there was an 82-fold increase in the conjugated bilirubin in serum in rifampicin-treated mice. In addition, an 8-fold increase in total bile acid in serum was observed after a seven-day administration of rifampicin. The integrity of hepatocyte ZO-1 and occludin was altered by a seven-day administration of rifampicin. Importantly, the integrity and intensity of hepatocyte tight junctions were altered as early as 30 min after a single dose of rifampicin. The expression of hepatic ZO-1 and ZO-2 mRNA was significantly decreased, beginning as early as 30 min and remaining a lower level 12 h after a single dose of rifampicin. Taken together, these results suggest that the altered integrity and internalization of hepatocyte tight junctions are associated with rifampicin-induced cholestasis.
AuthorsXi Chen, Cheng Zhang, Hua Wang, Juan Xu, Zi-Hao Duan, Ying Zhang, Tao Yu, Wei Wei, De-Xiang Xu, Jian-Ming Xu
JournalToxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 240 Issue 1 Pg. 26-36 (Oct 01 2009) ISSN: 1096-0333 [Electronic] United States
PMID19577586 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Rifampin
Topics
  • Administration, Oral
  • Animals
  • Cholestasis, Intrahepatic (chemically induced, metabolism, pathology)
  • Female
  • Hepatocytes (drug effects, metabolism, pathology)
  • Mice
  • Microscopy, Confocal
  • Rifampin (administration & dosage, toxicity)
  • Tight Junctions (drug effects, metabolism, pathology)

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