Shaw Patrick J, Beggs Kevin M, Sparkenbaugh Erica M, Dugan Christine M, Ganey Patricia E, Roth Robert A
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
Toxicol Sci. 2009 Oct;111(2):288-301. doi: 10.1093/toxsci/kfp163. Epub 2009 Jul 28.
Therapy employing the fluoroquinolone antibiotic, trovafloxacin (TVX) was curtailed due to idiosyncratic hepatotoxicity. Previous studies in mice showed that a nonhepatotoxic inflammatory stress induced by tumor necrosis factor alpha (TNF) synergized with a nonhepatotoxic dose of TVX to cause liver injury. The purpose of this study was to explore mechanisms by which TVX interacts with TNF to cause liver injury. TVX pretreatment prolonged the peak of plasma TNF after its administration. This prolongation of TNF by TVX was critical to the development of hepatotoxicity. The prolongation of TNF concentration in plasma was primarily due to reduced clearance when compared with secondary biosynthesis. TNF is cleared from plasma by binding to soluble TNF receptors (TNFRs) which are eliminated by the kidney; however, the plasma concentrations of soluble TNFRs were not reduced, and biomarkers of renal dysfunction were not elevated in TVX/TNF-treated mice. Two injections of TNF mimicked the prolongation of the TNF peak by TVX and caused liver injury, but injury was less severe than after TVX/TNF coexposure. TVX enhanced the induction of proinflammatory cytokines by TNF. Additionally, TVX sensitized Hepa1c1c7 cells to TNF-induced killing in a concentration-dependent manner and increased both potency and efficacy of TNF to activate effector caspases that were critically involved in cell death from TVX/TNF coexposure. In summary, TVX reduced the clearance of TNF independent of either receptor shedding or kidney dysfunction. Additionally, TVX interacted with TNF to enhance inflammation and sensitize hepatocytes to TNF-induced cell death.
由于特异质性肝毒性，使用氟喹诺酮抗生素曲伐沙星（TVX）的治疗被终止。先前在小鼠中的研究表明，由肿瘤坏死因子α（TNF）诱导的非肝毒性炎症应激与非肝毒性剂量的TVX协同作用会导致肝损伤。本研究的目的是探索TVX与TNF相互作用导致肝损伤的机制。TVX预处理延长了给药后血浆TNF的峰值。TVX对TNF的这种延长对肝毒性的发展至关重要。与次要生物合成相比，血浆中TNF浓度的延长主要是由于清除率降低。TNF通过与可溶性TNF受体（TNFRs）结合而从血浆中清除，这些受体由肾脏清除；然而，在TVX/TNF处理的小鼠中可溶性TNFRs的血浆浓度并未降低，并且肾功能障碍的生物标志物也未升高。两次注射TNF模拟了TVX对TNF峰值的延长并导致肝损伤，但损伤程度比TVX/TNF共同暴露后轻。TVX增强了TNF对促炎细胞因子的诱导。此外，TVX以浓度依赖的方式使Hepa1c1c7细胞对TNF诱导的杀伤敏感，并增加了TNF激活效应半胱天冬酶的效力和功效，这些半胱天冬酶在TVX/TNF共同暴露导致的细胞死亡中起关键作用。总之，TVX降低了TNF的清除率，与受体脱落或肾功能障碍无关。此外，TVX与TNF相互作用以增强炎症并使肝细胞对TNF诱导的细胞死亡敏感。
