Inflammation and idiosyncratic drug reactions: Inflammatory mechanisms and interactions in a murine model of trovafloxacin hepatotoxicity.

摘要

Drug-induced liver injury is the leading cause of acute liver failure in the United States and is a major concern for both public health and the pharmaceutical industry. Idiosyncratic adverse drug reactions (IADRs), a rare form of drug-induced liver injury, have been the reason for the majority of postmarket regulatory actions on drugs. The liver is often a target of IADRs. IADRs are characterized by the toxicity being unrelated to the pharmacology of the drug and do not demonstrate obvious dose or time dependence. The erratic occurrence and lack of mechanistic evidence makes IADRs very difficult to predict. Hepatotoxicity induced by the fluoroquinolone antibiotic trovafloxacin (TVX) exhibited these characteristics. The mechanism underlying TVX-induced idiosyncratic hepatotoxicity is unknown. We and others have hypothesized that an inflammatory stress, commonplace and erratic in people, could alter the threshold for toxicity of certain drugs precipitating an IADR.;This dissertation tested the hypothesis that an inflammatory stress could precipitate idiosyncrasy-like TVX hepatotoxicity in mice. Administration of a nonhepatotoxic dose of TVX 3 h before a nonhepatotoxic dose of either lipopolysaccharide (LPS) or peptidoglycan-lipoteichoic acid mixture caused significant hepatocellular necrosis and apoptosis. Levofloxacin (LVX), a fluoroquinolone antibiotic without IADR liability in humans, did not interact with LPS to cause hepatotoxicity. The remaining studies focused on understanding the mechanisms underlying TVX/LPS-induced liver injury.;Gene expression analysis at a time before the onset of liver injury segregated mice to their respective treatment groups. Therefore, gene expression analysis was able to distinguish TVX/LPS-treated mice from all other treatment groups.;Furthermore, LPS-induced increases in TNFalpha, IFNgamma, thrombin activation, PAI-1 and VEGF were enhanced by TVX. The progression of TVX/LPS-induced liver injury was dependent on PMN activation, TNFalpha, IFNgamma, thrombin activation, PAI-1 and VEGF. Based on this finding, mice were killed at a time near the onset of liver injury to explore how these mediators of inflammation interact with one another and the cascade of events which leads to TVX/LPS-induced hepatotoxicity. TNFalpha, IFNgamma, PAI-1 and VEGF potentially interacted to form several cycles of dysregulated inflammation. These potential vicious cycles of inflammation might be involved in TVX/LPS-induced liver injury.;In summary, novel proinflammatory properties and potential cycles of inflammation were identified which might be involved in various models of inflammatory tissue injury. Additionally, these studies support the possibility of predicting and identifying mechanisms underlying IADRs by utilization of a drug/LPS coexposure model.