Modeling xenobiotic susceptibility to hepatotoxicity using an in vitro oxidative stress inflammation model

Evidence suggests xenobiotic exposure during periods of inflammation can increase an individual's susceptibility to toxicity. The present study aimed to validate an in-vitro inflammatory model to identify compounds that increase hepatotoxicity during inflammation. Using freshly isolated hepatocytes exposed to a low nontoxic flow of H2O2 using glucose (G) and glucose oxidase (GO) and supplementing it with either peroxidase or Fe(II), the effects of inflammation on 2 classes of drugs known to cause hepatotoxicity were examined: nitroaromatics (nimesulide, nilutamide, flutamide) and aromatic amines (clozapine, thioridazine). Co-incubation with G/GO and the nitroaromatics increased toxicity that was further increased when peroxidase was present. While the aromatic amines did not increase cytotoxicity with G/GO alone, they demonstrated significant increases in cytotoxicity when incubated with peroxidase+G/GO. Liver injury is commonly observed with alcohol abusers; therefore, the effects of inflammation on ethanol, and its metabolite acetaldehyde, were observed. Both ethanol and acetaldehyde increased cytotoxicity, which was further increased when Fe(II) was present. These results implicate H2O2, a cellular mediator of inflammation, as a potential risk factor for hepatotoxicity. A H2O2-enhanced hepatocyte-system in the presence of peroxidase or Fe(II) may prove useful for a more robust screening of xenobiotics for assessing potential toxicity associated with inflammation.