Coexposure to trovafloxacin and lipopolysaccharide causes tumor necrosis factor alpha ‐dependent liver injury: a murine model of idiosyncratic liver injury.

Abstract

Concurrent inflammation caused by lipopolysaccharide (LPS) renders rats susceptible to hepatotoxicity from several drugs known to cause idiosyncratic adverse drug reactions (IADRs) in humans. Among these is trovafloxacin (TVX), a fluoroquinolone antibiotic. We explored whether this hepatotoxic TVX/LPS interaction occurs in mice and if tumor necrosis factor α (TNFα) is critical in liver injury development. Treatment with TVX alone up to 200 mg/kg did not increase plasma alanine aminotransferase (ALT) activity, a biomarker of liver injury. When mice were exposed to a nontoxic dose of LPS (2 x 10^6 EU/kg) 3 hours after TVX, a dose-dependent increase in ALT activity was observed with significant liver injury occurring at 150 mg/kg TVX. Liver damage was corroborated by histopathologic evaluation of the tissue. Levofloxacin, a fluoroquinolone antibiotic that does not cause human IADRs, did not interact with LPS to cause liver injury. Prior administration of pentoxifylline (PTX; 200 mg/kg), an inhibitor of TNFα transcription, treatment led to a significant decrease in ALT activity and reduced histopathologic evidence of liver damage. In summary, TVX/LPS cotreatment caused pronounced hepatotoxicity in mice and PTX pretreatment significantly decreased TNFα plasma concentrations and provided protection from TVX/LPS-induced liver injury (Supported by NIH grant DK061315.)