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Vol. 303, Issue 2, 461-467, November 2002
Division of Gastroenterology and Hepatology, Mayo Medical School,
Clinic, and Foundation, Rochester, Minnesota
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL),
a potential chemotherapeutic agent for cancer, is not thought to be
hepatotoxic. We have recently demonstrated, however, that bile acids
increase TRAIL-R2/DR5 expression in a human liver cell line and
render these cells susceptible to TRAIL-mediated apoptosis. These data
suggest TRAIL may be hepatotoxic in cholestasis. The aim of this study
was to directly assess TRAIL hepatotoxicity in bile duct-ligated mice,
a model of extrahepatic cholestasis. Bile duct-ligated mice (3 days)
were used for these studies. TRAIL-R2/DR5 expression was assessed by
real-time and immunoblot analysis. The TRAIL death-inducing signaling
complex (DISC) was evaluated by immunoprecipitation and immunoblot
techniques. Bile duct ligation increased both liver TRAIL-R2/DR5 mRNA
and protein expression (>10-fold). Following TRAIL
administration (60 µg/mouse, i.v.) to bile duct ligation (BDL)
mice, terminal deoxynucleotidyl transferase dUTP nick-end
labeling-positive hepatocytes, liver tissue caspase 3-like
activity, and serum alanine aminotransferase values increased significantly compared with vehicle-treated BDL mice. The effect of TRAIL on the liver was direct, as the TRAIL DISC (Fas-associated death domain and procaspase 8 protein) was detected in liver tissue. TRAIL-mediated hepatocyte apoptosis in bile duct-ligated mice was
associated with significant hepatotoxicity, as assessed by histopathology, although there was no animal mortality. In conclusion, these data define conditions under which TRAIL is hepatotoxic.
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