Basic–liver, pancreas, and biliary tractc-Jun N-Terminal Kinase Plays a Major Role in Murine Acetaminophen Hepatotoxicity
Section snippets
Materials
JNK inhibitor SP600125, p38 inhibitor SB203580, and ERK inhibitor PD98059 were purchased from Calbiochem (San Diego, CA). Antisense oligonucleotides (ASO) targeting mouse JNK1 (Isis 104492), JNK2 (Isis 101759), and a chemical control oligonucleotide (Isis 141923) were synthesized as 20 nucleotide, uniform phosphorothioate chimeric oligonucleotides and purified as previously described.4 The oligonucleotides used in these studies were chimeric oligonucleotides containing 5 nuclease resistant
Effect of JNK Inhibitor, SP600125, on APAP-Induced Toxicity in Murine Hepatocytes
First, we confirmed the previous finding that 1-hour pretreatment with JNK inhibitor (20 μmol/L) provided significant protection (>50%) against 5 mmol/L APAP-induced necrosis (not shown). Equimolar concentrations of inhibitors of MAP kinases, p38 and Erk, did not provide significant protection against APAP-induced necrosis determined after 15 hours (not shown). Protection by the JNK inhibitor was not accompanied by a change in the extent of maximum GSH depletion Figure 1 (Figure 1A) or [14C]
Discussion
Conflicting evidence for a role of JNK in APAP toxicity has been published previously. In C6 glioma cells, APAP cytotoxicity was dependent on JNK activity,25 whereas, in Hep G2 cells, APAP treatment caused JNK activation, but inhibition of JNK did not afford protection against cytotoxicity.26 However, the findings in the present report unequivocally establish a role for JNK activation in APAP hepatotoxicity. In both cultured hepatocytes and in vivo livers, treatment with APAP induced a
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Supported by NIH grants DK30312 and DK48522; a postdoctoral training award from the Los Angeles Chapter of The American Liver Foundation (to B.K.G.); a postdoctoral training award from the Garrie-Budnick Foundation (to D.H.); and an NIH KO1 award (DK67149; to Z-X.L.).