title: Modest inflammation enhances diclofenac hepatotoxicity in rats: role of neutrophils and bacterial translocation.
abstract: Idiosyncratic adverse drug reactions (IADRs) represent an important human health problem, yet animal models for preclinical prediction of these reactions are lacking. Recent evidence in animals suggests that some IADRs arise from drug interaction with an inflammatory episode that renders the liver sensitive to injury. Diclofenac (DCLF) is one of those drugs for which the clinical use is limited by idiosyncratic liver injury. We tested the hypothesis that modest inflammation triggered in rats by a small dose of lipopolysaccharide (LPS) renders a nonhepatotoxic dose of DCLF injurious to liver. Cotreatment of rats with nonhepatotoxic doses of LPS and DCLF resulted in elevated serum alanine aminotransferase activity and liver histopathologic changes 6 h after DCLF administration. Neither LPS nor DCLF alone had such an effect. Gene array analysis of livers revealed a unique gene expression pattern in the LPS/DCLF-cotreated group compared with groups given either agent alone. Antiserum-induced neutrophil (PMN) depletion in LPS/DCLF-cotreated rats protected against liver injury, demonstrating a role for PMNs in the pathogenesis of this LPS/DCLF interaction. Gut sterilization of LPS/DCLF-treated rats did not protect against liver injury. In contrast, gut sterilization did attenuate liver injury caused by a large, hepatotoxic dose of DCLF, suggesting that hepatotoxicity induced by large doses of DCLF is caused in part by its ability to increase intestinal permeability to endotoxin or other bacterial products. These results demonstrate that inflammation-DCLF interaction precipitates hepatotoxicity in rats and raise the possibility of creating animal models that predict human IADRs.
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Deng
authors.forename: Robert F
authors.initials: RF
authors.lastname: Stachlewitz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Liguori
authors.forename: Eric A G
authors.initials: EA
authors.lastname: Blomme
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Waring
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.forename: Jane F
authors.initials: JF
authors.lastname: Maddox
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D018988:Bacterial Translocation / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury / Q000382:microbiology / Q000473:pathology*; D054426:Chemokine CXCL2; D004008:Diclofenac / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000382:microbiology; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000473:pathology*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000382:microbiology; D008297:Male; D015846:Monokines / Q000097:blood; D009504:Neutrophils / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054426:Chemokine CXCL2; D008070:Lipopolysaccharides; D015846:Monokines; D004008:Diclofenac; D012313:RNA; D000410:Alanine Transaminase