Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha
Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha
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DOI：
10.1093/toxsci/kfm218
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发表时间：
2007-11-01
影响因子：
3.8
通讯作者：
Roth, Robert A.
中科院分区：
文献类型：
--
作者：
Shaw, Patrick J.;Hopfensperger, Marie J.;Roth, Robert A.
特异性药物不良反应（IADRs）发生在一小部分患者中，与药物的药理作用无关，与药物暴露剂量或持续时间无明显关系。肝脏通常是这些反应的目标。它们发生的原因尚不清楚。一种可能性是，间歇性炎症应激与药物相互作用，导致毒性反应。我们开始确定脂多糖（LPS）是否使小鼠对曲瓦沙星（TVX）敏感，曲瓦沙星是一种与人类特异性肝毒性相关的氟喹诺酮类抗生素，以及细胞因子肿瘤坏死因子α (TNF α)是否参与肝损伤的发展。雄性小鼠用无毒剂量的TVX治疗，3小时后用无肝毒性剂量的LPS治疗。通过血浆丙氨酸转氨酶活性和组织病理学检查发现，TVX和LPS共同暴露导致肝损伤显著增加。相比之下，小鼠与LPS和左氧氟沙星（LVX）（一种不会引起人类IADRs的氟喹诺酮类药物）共同暴露没有肝毒性。血浆中TNF - α浓度的测量显示，在肝损伤发生之前和发生时，TVX/ lps处理的小鼠血浆中TNF - α浓度显着选择性增加。用己酮茶碱抑制TNF α转录或依那西普抑制TNF α活性均可显著减轻TVX/ lps诱导的肝损伤。结果表明，小鼠模型能够区分具有和不具有引起特异性肝损伤倾向的药物，肝毒性依赖于TNF α。
Idiosyncratic adverse drug reactions (IADRs) occur in a small subset of patients, are unrelated to the pharmacological action of the drug, and occur without an obvious relationship to dose or duration of drug exposure. The liver is often the target of these reactions. Why they occur is unknown. One possibility is that episodic inflammatory stress interacts with the drug to precipitate a toxic response. We set out to determine if lipopolysaccharide (LPS) renders mice sensitive to trovafloxacin (TVX), a fluoroquinolone antibiotic linked to idiosyncratic hepatotoxicity in humans and if the cytokine tumor necrosis factor-alpha (TNF alpha) is involved in the development of liver injury. Male mice were treated with a nontoxic dose of TVX followed 3 h later by a nonhepatotoxic dose of LPS. Coexposure to TVX and LPS led to a significant increase in liver injury as determined by plasma alanine aminotransferase activity and histopathological examination. In contrast, coexposure of mice to LPS and levofloxacin (LVX), a fluoroquinolone without liability for causing IADRs in humans, was not hepatotoxic. Measurements of TNF alpha concentration in the plasma revealed a significant, selective increase in TVX/LPS-treated mice at times prior to and at the onset of liver injury. Treatment with either pentoxifylline to inhibit TNF alpha transcription or etanercept to inhibit TNF alpha activity significantly reduced TVX/LPS-induced liver injury. The results suggest that the model in mice is able to distinguish between drugs with and without the propensity to cause idiosyncratic liver injury and that the hepatotoxicity is dependent on TNF alpha.