Modeling xenobiotic susceptibility to hepatotoxicity using an in vitro oxidative stress inflammation model
Modeling xenobiotic susceptibility to hepatotoxicity using an in vitro oxidative stress inflammation model
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DOI：
10.1139/cjpp-2012-0255
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发表时间：
2013-03-01
影响因子：
2.1
通讯作者：
O'Brien, Peter
中科院分区：
文献类型：
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作者：
MacAllister, Stephanie L.;Maruf, Abdullah A.;O'Brien, Peter
有证据表明，在炎症期间暴露于异生物质会增加个体对毒性的敏感性。本研究旨在验证体外炎症模型，以确定在炎症期间增加肝毒性的化合物。使用新鲜分离的肝细胞暴露于低无毒流的H2 O2，使用葡萄糖（G）和葡萄糖氧化酶（GO），并补充过氧化物酶或Fe（II），炎症对2类已知引起肝毒性的药物的影响进行了检查：硝基芳烃（尼美舒利，尼鲁米特，氟替卡松）和芳香胺（氯氮平，硫利达嗪）。与G/GO和硝基芳族化合物共孵育增加了毒性，当过氧化物酶存在时进一步增加。虽然芳族胺不增加单独的G/GO的细胞毒性，但当与过氧化物酶+G/GO孵育时，它们表现出细胞毒性的显著增加。酒精滥用者通常会观察到肝损伤;因此，观察到炎症对乙醇及其代谢物乙醛的影响。乙醇和乙醛都增加了细胞毒性，当Fe（II）存在时，细胞毒性进一步增加。这些结果暗示H2 O2，炎症的细胞介质，作为肝毒性的潜在危险因素。在过氧化物酶或Fe（II）存在下的H2 O2增强的肝细胞系统可能被证明可用于更稳健地筛选外源性物质，以评估与炎症相关的潜在毒性。
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.