Modeling xenobiotic susceptibility to hepatotoxicity using an in vitro oxidative stress inflammation model1
2013
MacAllister, Stephanie L. | Maruf, Abdullah A. | Wan, Luke | Chung, Erin | O'Brien, Peter
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.
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