PT  - JOURNAL ARTICLE
AU  - Wei Zou
AU  - Kevin M. Beggs
AU  - Erica M. Sparkenbaugh
AU  - A. Daniel Jones
AU  - Husam S. Younis
AU  - Robert A. Roth
AU  - Patricia E. Ganey
TI  - Sulindac Metabolism and Synergy with Tumor Necrosis Factor-α in a Drug-Inflammation Interaction Model of Idiosyncratic Liver Injury
AID  - 10.1124/jpet.109.156331
DP  - 2009 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 114--121
VI  - 331
IP  - 1
4099  - http://jpet.aspetjournals.org/content/331/1/114.short
4100  - http://jpet.aspetjournals.org/content/331/1/114.full
SO  - J Pharmacol Exp Ther2009 Oct 01; 331
AB  - 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-α (TNF-α) in plasma was significantly increased by LPS at 1 h, and SLD enhanced this response. Etanercept, a soluble TNF-α receptor, reduced SLD/LPS-induced liver injury, suggesting a role for TNF-α. 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-α augmented the cytotoxicity of SLD sulfide in primary hepatocytes and HepG2 cells. These results suggest that TNF-α can enhance SLD sulfide-induced hepatotoxicity, thereby contributing to liver injury in SLD/LPS-cotreated rats. © 2009 by The American Society for Pharmacology and Experimental Therapeutics