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.