Loading…
Sulindac Metabolism and Synergy with Tumor Necrosis Factor-α in a Drug-Inflammation Interaction Model of Idiosyncratic Liver Injury
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...
Saved in:
Published in: | The Journal of pharmacology and experimental therapeutics 2009-10, Vol.331 (1), p.114 |
---|---|
Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | 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. |
---|---|
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.109.156331 |