Lipopolysaccharide and Trovafloxacin Coexposure in Mice Causes Idiosyncrasy-Like Liver Injury Dependent on Tumor Necrosis Factor-Alpha

Abstract

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 (TNFalpha) 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 TNFalpha 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 TNFalpha transcription or etanercept to inhibit TNFalpha 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 TNFalpha.

Trovafloxacin Potentiation of Lipopolysaccharide-Induced Tumor Necrosis Factor Release from RAW 264.7 Cells Requires Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase

“…In mice, the maximal hepatotoxic response to TVX occurred when the animals were treated with TVX 3 hours before LPS exposure (Shaw et al, 2007). To approximate this exposure in vitro, RAW cells were exposed to TVX prior to LPS using the regimen depicted in Fig.…”

“…A defining characteristic of this model was that the liver injury depended upon TNF. Pharmacological intervention with pentoxifylline to inhibit TNF transcription or with etanercept to neutralize released TNF prevented the injury (Shaw et al, 2007). Studies in TNF receptor knockout mice supported a key role for TNF in TVX/LPS hepatotoxicity (Shaw et al, 2009b).…”

“…Among several hypotheses put forth to explain IDILI is the inflammatory stress hypothesis, which states that a mild inflammatory episode interacts with a drug, resulting in hepatotoxicity (Shaw et al, 2010). Animal models based on this hypothesis have been developed for several drugs that have caused IDILI in humans, including chlorpromazine, ranitidine, amiodarone, doxorubicin, sulindac, and trovafloxacin (TVX) (Buchweitz et al, 2002;Luyendyk et al, 2003;Shaw et al, 2007;Hassan et al, 2008;Zou et al, 2009;Lu et al, 2012). In each of these models, bacterial lipopolysaccharide (LPS) was used to cause a modest, nontoxic, acute inflammatory episode.…”

“…Soon after its introduction into the market, TVX use was severely restricted due to 14 cases of acute liver failure, of which six were fatal (Ball et al, 1999). An animal model of TVX IDILI was established in which mice coexposed to nontoxic doses of TVX and LPS developed pronounced hepatocellular injury (Shaw et al, 2007). A defining characteristic of this model was that the liver injury depended upon TNF.…”

Idiosyncratiques et « omiques » peuvent-ils rimer ?

“…Ces augmentations entraîneraient une accumulation des neutrophiles responsables de l'hépatotoxicité. Avec une approche similaire, les mêmes effets ont été observés chez des souris traitées par LPS + TVX [24], et il a été montré que l'IL-18 et l'IFN- (interféron-) jouaient un rôle crucial dans l'hépatotoxicité [25]. Cette approche identifie donc des pistes mécanistiques et des biomarqueurs de la toxicité chez l'homme.…”