| Idiosyncratic adverse drug response is a type of adverse reaction that occurs in a minority of patients during drug therapy. Liver is one of the major organ targets. All of the nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with hepatic idiosyncratic adverse drug reactions (IADRs) in patients, and the risk from sulindac (SLD) is reported to be 5-10 fold greater than for NSAIDs as a class. However, the mechanism of SLD-induced hepatotoxicity has not been clarified because of the lack of experimental animal models. Previous studies suggest that inflammatory stress is a susceptibility factor for IADRs. The work in this dissertation supports this hypothesis. Cotreatment of rats with lipopolysaccharide (LPS), which induces modest inflammation, and SLD resulted in liver necrosis, whereas neither LPS nor SLD was hepatotoxic alone. After we developed a SLD- inflammation interaction model of idiosyncratic liver injury by treating rats with SLD and LPS, the mechanisms of SLD/LPS- induced liver injury were investigated. SLD/LPS cotreatment causes an increase in the production of tumor necrosis factor-alpha (TNF), activation of the hemostatic system and of neutrophils (PMNs) as well as oxidative stress in the liver. Neutralization of TNF, anticoagulant administration, PMN depletion or antioxidant treatment attenuated liver injury in this model. Results of neutralization or inhibition studies in vivo and in vitro suggest roles for TNF, the hemostatic system, PMNs and oxidative stress in the pathogenesis of liver injury-induced by SLD/LPS. Moreover, these mediators are not independent players. They contribute to liver injury by interacting with each other and with the SLD toxic metabolite, SLD sulfide. The studies in this dissertation provide an understanding of mechanisms of liver injury resulting from SLD- inflammation interaction. |
