| Idiosyncratic reactions occur in a small fraction of people taking a drug. The liver is a frequent target. For the vast majority of drugs associated with these reactions, including the histamine2 (H2) receptor antagonist ranitidine, the mechanism of toxicity is unknown. Inasmuch as a modest inflammatory response can render rats susceptible to hepatotoxic effects of several xenobiotics, inflammation might also be a determinant of sensitivity to drug toxicity. This dissertation tested the hypothesis that an inflammatory response caused by a nonhepatotoxic dose of bacterial lipopolysaccharide (LPS) could precipitate idiosyncrasy-like RAN hepatotoxicity in rats. Administration of a small dose of LPS (44 x 106 EU/kg, iv) two hours before a nonhepatotoxic dose of RAN (30 mg/kg, iv) caused significant hepatotoxicity characterized by midzonal hepatocellular oncotic necrosis, the onset of which occurred between 2--3 h after drug treatment. These histopathologic findings and changes in clinical chemistry resembled idiosyncratic RAN hepatotoxicity in people. The H2-antagonist famotidine (FAM), which is not associated with idiosyncratic hepatotoxicity, was not rendered toxic by LPS cotreatment. Hepatic gene expression was evaluated at a time before injury in rats treated with LPS and/or RAN, and hierarchical clustering of active genes segregated rats to their respective treatment groups. Several genes related to hypoxia, inflammation and cell death were expressed to a greater degree in LPS/RAN-treated rats compared to either agent given alone. This pattern of expression for plasminogen activator inhibitor-1 (PAI-1) was confirmed by real-time PCR and was mirrored by the PAM concentration in the plasma of LPS/RAN-treated rats. Consistent with the antifibrinolytic function of PAM, hepatic fibrin deposition was observed only in livers of LPS/RAN-treated rats. To determine if hepatic fibrin deposition was a consequence of impaired fibrinolysis, coagulation system activation, or both, several biomarkers of coagulation were evaluated. Changes in serum hyaluronic acid, an indicator of altered sinusoidal endothelial cell (SEC) homeostasis, thrombin-antithrombin dimers, and fibrinogen suggested coagulation system activation in LPS/RAN-treated rats. Liver injury and hepatic fibrin deposition were attenuated by both the fibrinolysic agent streptokinase and the anticoagulant heparin, indicating that the hemostatic system is involved in LPS/RAN-induced liver injury. Liver hypoxia, one consequence of fibrin deposition, was observed only in livers of LPS/RAN-treated rats and was reduced by heparin coadministration. Neutrophils (PMNs) accumulated in livers of LPS/RAN-treated rats, and killing of primary rat hepatocytes by PMN elastase in vitro was augmented under hypoxic conditions. The results suggest that the hemostatic system is important for liver injury in LPS/RAN-treated rats and are consistent with resultant hypoxia interacting with inflammatory mediators to cause hepatocellular injury. Furthermore, these studies support the possibility of predicting and understanding the mechanisms of some idiosyncratic drug reactions by utilization of a drug/LPS-cotreatment model. |
