Role of the paracrine liver endothelin system in the pathogenesis of CCl4-induced liver injury

This study analyzed if the paracrine liver endothelin system participates in the pathogenesis of CCl₄-induced hepatotoxicity. Wistar Kyoto rats were divided into four groups: a bosentan (mixed endothelin ET_A and ET_B receptor antagonist) treated group with CCl₄ intoxication, a vehicle treated group with CCl₄ intoxication, a nontreated control group and a bosentan treated control group. Hepatotoxicity was assessed by determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) followed by histopathological examinations. Tissue endothelin-1 concentrations and expression of endothelin receptor subtypes were analyzed. The tissue levels of endothelin-1 in the liver of rats with CCl₄ intoxication were significantly higher than those in normal rats. Scatchard analysis revealed no differences in the density and binding constant of endothelin ET_A and ET_B receptor between rats with CCl₄ intoxication and controls. Bosentan treatment of rats undergoing CCl₄ inhalation resulted in a significant protection against elevation of ALT, AST, LDH and bilirubin. Histopathological examination of liver sections for necrotic, swollen and lipid-laden cells revealed findings that were in agreement with the serum enzyme data. In conclusion, this study showed that the paracrine endothelin system is involved in the pathogenesis of CCl₄-induced hepatotoxicity and that the blockade of the stimulated liver endothelin system reduces CCl₄-induced liver injury.