Altered integrity and decreased expression of hepatocyte tight junctions in rifampicin-induced cholestasis in mice.
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.
Chen
Xi
X
Department of Gastroenterology, First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
Zhang
Cheng
C
Wang
Hua
H
Xu
Juan
J
Duan
Zi-Hao
ZH
Zhang
Ying
Y
Yu
Tao
T
Wei
Wei
W
Xu
De-Xiang
DX
Xu
Jian-Ming
JM
D000284:Administration, Oral; D000818:Animals; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018613:Microscopy, Confocal; D012293:Rifampin / Q000008:administration & dosage / Q000633:toxicity*; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*
D012293:Rifampin