title: Modeling xenobiotic susceptibility to hepatotoxicity using an in vitro oxidative stress inflammation model.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: MacAllister
authors.forename: Abdullah A
authors.initials: AA
authors.lastname: Maruf
authors.forename: Luke
authors.initials: L
authors.lastname: Wan
authors.forename: Erin
authors.initials: E
authors.lastname: Chung
authors.forename: Peter
authors.initials: P
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D018836:Inflammation Mediators; D008297:Male; D008956:Models, Chemical; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: D018836:Inflammation Mediators; D015262:Xenobiotics