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-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.
- NSAID, nonsteroidal anti-inflammatory drug
- ALT, alanine aminotransferase
- DMSO, dimethyl sulfoxide
- IADR, idiosyncratic adverse drug reaction
- LDH, lactate dehydrogenase
- LPS, lipopolysaccharide
- SLD, sulindac
- TNF-α, tumor necrosis factor-α
- UPLC, ultra performance liquid chromatography
- LC/MS/MS, liquid chromatography-tandem mass spectrometry
- GI, gastrointestinal
- NF-κB, nuclear factor κB
- ROS, reactive oxygen species
- EU, endotoxin units.
Footnotes
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This work was supported by the National Institutes of Health [Grants GM075865, DK061315] and a collaborative agreement with Pfizer, Inc. E.M.S. was supported by the National Institutes of Health [Training Grant T32ES007255]. The Quattro Premier UPLC/MS/MS instrument was purchased with funds from National Science Foundation [Grant DBI-0619489].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.156331
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ABBREVIATIONS:
- Received May 18, 2009.
- Accepted July 27, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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