title: Enhanced hepatotoxicity by acetaminophen in Vanin-1 knockout mice is associated with deficient proliferative and immune responses.
abstract: Pretreatment with clofibrate, a peroxisome proliferator-activated receptor alpha (PPARa) agonist, protects mice from acetaminophen (APAP) injury. Protection is not due to alterations in APAP metabolism and is dependent on PPARa expression. Gene array analysis revealed that mice receiving clofibrate have enhanced hepatic Vanin-1 (Vnn1) gene expression, a response that is also PPARa dependent.
  
  
  
  We examined the role of Vnn1 by comparing the responses of Vnn1 knockout and wild-type mice following APAP hepatotoxicity. APAP metabolism, hepatotoxicity, and compensatory hepatocyte proliferation and immune responses were assessed.
  
  
  
  Vnn1 knockout mice are more susceptible to APAP hepatotoxicity despite no differences in hepatic glutathione content, gene expression of APAP metabolizing enzymes, or hepatic capacity to bioactivate or detoxify APAP ex vivo. Together, these data strongly suggest that the susceptibility of Vnn1 knockout mice is not due to differences in APAP metabolism. Immunochemistry revealed a lack of proliferating cell nuclear antigen-positive hepatocytes and F4/80-positive macrophages in and around areas of centrilobular necrosis in APAP-treated Vnn1 knockouts. Hepatic gene induction of pro-inflammatory cytokines was either significantly reduced or completely blunted in these mice. This was correlated with a reduction in early recruitment of cells positive for granulocyte differentiation antigen 1 or integrin alpha M. Heightened toxicity was also observed in CCl4 and ConA hepatitis models in the absence of Vnn1.
  
  
  
  These results indicate that mice lacking Vnn1 have deficiencies in compensatory repair and immune responses following toxic APAP exposure and that these mechanisms may contribute to the enhanced hepatotoxicity seen.
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA.
authors: Daniel W
authors: DW
authors: Ferreira
authors: Office of Translational Science, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors: Michael J
authors: MJ
authors: Goedken
authors: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, 13288 Marseille, France.
authors: Samuel
authors: S
authors: Rommelaere
authors: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, 13288 Marseille, France.
authors: Lionel
authors: L
authors: Chasson
authors: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, 13288 Marseille, France.
authors: Franck
authors: F
authors: Galland
authors: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, 13288 Marseille, France.
authors: Philippe
authors: P
authors: Naquet
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA. Electronic address: jose.manautou@uconn.edu.
authors: José E
authors: JE
authors: Manautou
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000494:pharmacology; D000581:Amidohydrolases / Q000172:deficiency* / Q000276:immunology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002994:Clofibrate / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000172:deficiency / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000276:immunology
chemical_list: D058851:GPI-Linked Proteins; D047493:PPAR alpha; D000082:Acetaminophen; D000581:Amidohydrolases; C022314:pantetheinase; D002994:Clofibrate
keywords: Clofibrate; Cysteamine; Liver; Pantetheine hydrolase; Peroxisome proliferators