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Toxicology. 2010 Jun 4;272(1-3):32-8. doi: 10.1016/j.tox.2010.03.015. Epub 2010 Apr 3.

Oxidative stress is important in the pathogenesis of liver injury induced by sulindac and lipopolysaccharide cotreatment.

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Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, United States.


Among currently prescribed nonsteroidal anti-inflammatory drugs, sulindac (SLD) is associated with the greatest incidence of idiosyncratic hepatotoxicity in humans. Previously, an animal model of SLD-induced idiosyncratic hepatotoxicity was developed by cotreating rats with a nonhepatotoxic dose of LPS. Tumor necrosis factor-alpha (TNF) was found to be critically important to the pathogenesis. In this study, the mechanism of liver injury induced by SLD/LPS cotreatment was further explored. Protein carbonyls, products of oxidative stress, were elevated in liver mitochondria of SLD/LPS-cotreated rats. The results of analyzing gene expression in livers of rats before the onset of liver injury indicated that genes associated with oxidative stress were selectively regulated by SLD/LPS cotreatment. Antioxidant treatment with either ebselen or dimethyl sulfoxide attenuated SLD/LPS-induced liver injury. The role of oxidative stress was further investigated in vitro. SLD sulfide, the toxic metabolite of SLD, enhanced TNF-induced cytotoxicity and caspase 3/7 activity in HepG2 cells. SLD sulfide also increased dichlorofluorescein fluorescence, suggesting generation of reactive oxygen species (ROS). Hydrogen peroxide and TNF cotreatment of HepG2 cells caused greater cytotoxicity than either treatment alone. Either antioxidant tempol or a pancaspase inhibitor Z-VAD-FMK decreased cell death as well as caspase 3/7 activity induced by SLD sulfide/TNF coexposure. These results indicate that SLD/LPS treatment causes oxidative stress in livers of rats and suggest that ROS are important in SLD/LPS-induced liver injury in vivo. Furthermore, ROS contribute to the cytotoxic interaction of SLD and TNF by activating caspase 3/7.

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