Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha.
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.
Shaw
Patrick J
PJ
Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
Hopfensperger
Marie J
MJ
Ganey
Patricia E
PE
Roth
Robert A
RA
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000068800:Etanercept; D024841:Fluoroquinolones / Q000008:administration & dosage; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D064704:Levofloxacin; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000008:administration & dosage; D015242:Ofloxacin / Q000008:administration & dosage; D010431:Pentoxifylline / Q000494:pharmacology / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism*
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D009287:Naphthyridines; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C482199:lipopolysaccharide, E coli O55-B5; D064704:Levofloxacin; C080163:trovafloxacin; D015242:Ofloxacin; D000410:Alanine Transaminase; D000068800:Etanercept; D010431:Pentoxifylline