Elucidation of Mechanism of Drug-Induced Liver Injury Based on Danger Hypothesis

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Animal models of inflammatory bowel disease were subjected to characterization of liver function under inflammatory conditions. Rats were treated intracolonically with 100 mg/kg trinitrobenzene sulfonic acid (TNBS), which induced hemorrhagic colitis. The colitis accompanies appearance of higher levels of portal endotoxin, interleukin-6 and nitric oxide metabolites, and decreases in contents and activities for hepatic CYP3A2. Nimesulide, a preferential COX-2 inhibitor protected rats with TNBS-colitis against the down-regulation of hepatic CYP3A2. Polymyxin B, which neutralizes endotoxin, curcumin, which has anti-inflammatory properties, and gadolinium chloride, which inactivates macrophages, attenuated the down-regulation of CYP3A2. These data suggest that endogenous substances leaked from damaged colon in the rats with TNBS-colitis activate Kupffer cells, leading to down-regulation of hepatic P450s. It is thus proposed that gut-derived inflammatory stimuli behave as "danger signal" in drug-induced liver effects. In other studies, role of covalent adduct in diclofenac hepatotoxicity was assessed by measuring metabolism-dependent covalent binding to hepatic microsomes from various animal species. Covalent binding [14C]diclofenac- derived radioactivity to microsomal protein after incubation with NADPH was higher in rats and mice than in humans. Similar to diclofenac '5-hydroxylation, the metabolism-dependent covalent binding was higher in male rats than in females, whereas this activity in human is very low. GSH, which lowers covalent binding, was more effective in male mice than in male rats. Thus, reactive metabolites can reach proteins other than P450 effectively in mice and may lead to hepatotoxicity, which was confirmed by in vivo study developing diclofenac-induced liver injury in mice. These findings suggest that both covalent binding to the specific targets and subsequent inflammatory stimuli are responsible for drug-induced hepatotoxicity.