Sulindac metabolite and TNFa interaction in liver injury induced by sulindac and lipopolysaccharide in rats

Abstract

Sulindac (SLD) is a nonsteroidal anti‐inflammatory drug (NSAID) that has been associated with a greater incidence of idiosyncratic hepatotoxicity in human patients than other NSAIDs. In previous studies, cotreatment of rats with SLD and a modestly inflammatory dose of lipopolysaccharide (LPS) led to liver injury, whereas neither SLD nor LPS alone caused liver damage. In studies presented here, the concentration of TNFα in plasma was significantly increased by LPS at 1 hr, and SLD enhanced this response. Etanercept, a soluble TNFα receptor, reduced SLD/LPS‐induced liver injury, suggesting a potential role for TNFα. SLD metabolites in plasma and liver were determined by LC/MS/MS. Cotreatment with LPS did not increase the concentrations of SLD or its metabolites, excluding the possibility that LPS contributed to liver injury through enhanced exposure to the SLD or its metabolites. The cytotoxicities of SLD and its sulfide and sulfone metabolites were compared in primary rat hepatocytes and HepG2 cells; SLD sulfide was more toxic in both types of cells than SLD or SLD sulfone. TNFα augmented the cytotoxicity of SLD sulfide in primary hepatocytes and HepG2 cells. These results suggest that TNFα enhances SLD sulfide‐induced hepatotoxicity, which might contribute to liver injury in SLD/LPS‐cotreated rats. (Supported by NIH GM075865 and ES004139.)