title: Effect of polyI:C cotreatment on halothane-induced liver injury in mice.
abstract: Drug-induced liver injury (DILI) is a challenging problem in drug development and clinical practice. Patient susceptibility to DILI is multifactorial, making these reactions difficult to predict and prevent. Clinical observations have suggested that concurrent bacterial and viral infections represent an important risk factor in determining patient susceptibility to developing adverse drug reactions, although the underlying mechanism is not clear. In the present study, we employed the viral RNA mimetic (polyinosinic-polycytidylic acid [polyI:C]) to emulate viral infection and examined its effect on halothane-induced liver injury. Although pretreatment of mice with polyI:C attenuated halothane hepatotoxicity due to its inhibitory effect on halothane metabolism, posttreatment significantly exacerbated liver injury with hepatocellular apoptosis being significantly higher than that in mice treated with polyI:C alone or halothane alone. The pan-caspase inhibitor z-VAD-fmk suppressed liver injury induced by polyI:C/posthalothane cotreatment, suggesting that the increased hepatocyte apoptosis contributes to the exacerbation of liver injury. Posttreatment with polyI:C also caused activation of hepatic Kupffer cells (KCs) and natural killer (NK) cells and upregulated multiple proapoptotic factors, including tumor necrosis factor-alpha (TNF-alpha), NK receptor group 2, member D (NKG2D), and Fas ligand (FasL). These factors may play important roles in mediating polyI:C-induced hepatocyte apoptosis.
  
  
  CONCLUSIONS
  This is the first study to provide evidence that concurrent viral infection can inhibit cytochrome (CYP)450 activities and activate the hepatic innate immune system to proapoptotic factors. DILI may be attenuated or exacerbated by pathogens depending on the time of infection.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Linling
authors.initials: L
authors.lastname: Cheng
authors.forename: Qiang
authors.initials: Q
authors.lastname: You
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.forename: Michael
authors.initials: M
authors.lastname: Holt
authors.forename: Christopher
authors.initials: C
authors.lastname: Franklin
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ju
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D061945:Caspase Inhibitors; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006221:Halothane / Q000633:toxicity*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007728:Kupffer Cells / Q000276:immunology / Q000502:physiology; D008099:Liver / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D011070:Poly I-C / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D053222:Fas Ligand Protein; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D011070:Poly I-C; D006221:Halothane