title: Role of c-Jun N-terminal kinase (JNK) in regulating tumor necrosis factor-alpha (TNF-alpha) mediated increase of acetaminophen (APAP) and chlorpromazine (CPZ) toxicity in murine hepatocytes.
abstract: Drug induced liver injury (DILI) accounts for more than 50% of the cases of acute liver failure in this country, and is the major cause of drug withdrawal from the market. DILI has been associated with the induction of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha). Pro-inflammatory cytokines activate the mitogen activated protein kinase, c-Jun-N-terminal kinase (JNK) in the liver. Recent studies have shown that JNK can regulate the hepatotoxicity of the analgesic, acetaminophen (APAP). Several reports have shown that inflammation induced by the endotoxin, lipopolysaccharide (LPS) augments the toxic response to hepatotoxicants in vivo. However, the mechanism by which inflammation alters drug-induced hepatotoxicity is not known. This study investigated the role of inflammatory mediators in regulating the toxicity of the hepatotoxic drugs, APAP or chlorpromazine (CPZ) in primary mouse hepatocytes. We found that, pre-treatment with TNF-alpha resulted in approximately 50 to 60% increase in alanine aminotransferase (ALT) levels by APAP or CPZ, while interleukin-1beta (IL-1beta) or IL6 treatments showed only 15-20% increase in ALT release. The bacterial components, LPS or lipoteichoic acid (LTA) increased ALT release by approximately 35 to 38% upon drug treatment of the hepatocytes. The JNK inhibitor, SP600125 significantly diminished APAP and CPZ toxicity with or without TNF-alpha. Pre-treatment with TNF-alpha resulted in prolonged activation of JNK (upto 2 hr) in the presence of APAP or CPZ. These results show that TNF-alpha is the major cytokine involved in sensitizing hepatocytes to APAP- or CPZ-induced hepatotoxicity, likely by a mechanism involving sustained activation of JNK.
authors.affiliation: University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, Houston, TX 77030, USA.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Gandhi
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.forename: Romi
authors.initials: R
authors.lastname: Ghose
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects*; D053583:Interleukin-1beta / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D048031:JNK Mitogen-Activated Protein Kinases; D002746:Chlorpromazine