title: Sulindac metabolism and synergy with tumor necrosis factor-alpha in a drug-inflammation interaction model of idiosyncratic liver injury.
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, further investigation of this animal model revealed that the concentration of tumor necrosis factor-alpha (TNF-alpha) in plasma was significantly increased by LPS at 1 h, and SLD enhanced this response. Etanercept, a soluble TNF-alpha receptor, reduced SLD/LPS-induced liver injury, suggesting a role for TNF-alpha. 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 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. TNF-alpha augmented the cytotoxicity of SLD sulfide in primary hepatocytes and HepG2 cells. These results suggest that TNF-alpha can enhance SLD sulfide-induced hepatotoxicity, thereby contributing to liver injury in SLD/LPS-cotreated rats.
authors.affiliation: Department of Microbiology and Molecular Genetics, Center for Integrative Toxicology, Michigan State University, East Lansing, 48824, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Beggs
authors.forename: Erica M
authors.initials: EM
authors.lastname: Sparkenbaugh
authors.forename: A Daniel
authors.initials: AD
authors.lastname: Jones
authors.forename: Husam S
authors.initials: HS
authors.lastname: Younis
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000473:pathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D008070:Lipopolysaccharides / Q000378:metabolism / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013467:Sulindac / Q000378:metabolism* / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D013467:Sulindac