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Hepatotoxicity mediated by pyrazole (cytochrome P450 2E1) plus tumor necrosis factor alpha treatment occurs in c‐Jun N‐terminal kinase 2−/− but not in c‐Jun N‐terminal kinase 1−/− mice

Cytochrome P450 2E1 (CYP2E1) induction and tumor necrosis factor alpha (TNF‐α) production are key risk factors in alcoholic liver injury. Increased oxidative stress from CYP2E1 induction by pyrazole in vivo sensitizes the liver to TNF‐α‐induced hepatotoxicity by a mechanism involving the activation of c‐jun N‐terminal kinase (JNK) and mitochondrial damage. The aim of this study was to evaluate whether JNK1 or JNK2 plays a role in this potentiated hepatotoxicity. Wild‐type (WT), jnk1−/−, and jnk2−/− mice were used to identify changes of hepatotoxicity, damage to mitochondria, and production of oxidative stress after pyrazole plus TNF‐α treatment. Increased serum alanine aminotransferase, inflammatory infiltration, and central necrosis were observed in the jnk2−/− and WT mice treated with pyrazole plus TNF‐α, but not in the jnk1−/− mice. Pyrazole elevated the activity and protein level of CYP2E1 in all mice. There was a significant increase of malondialdehyde, 4‐hydroxynonenal adducts, 3‐nitrotyrosine, and inducible nitric oxide synthase in the jnk2−/− and WT mice, compared to the jnk1−/− mice, upon pyrazole plus TNF‐α treatment, or compared to mice treated with either pyrazole alone or TNF‐α alone. The antioxidants, catalase, phospholipid hydroperoxide glutathione peroxidase, thioredoxin, and glutathione were lowered, and cytochrome c was released from the mitochondria in the jnk2−/− and WT mice. Mitochondrial production of superoxide was increased in the jnk2−/− and WT mice, compared to the jnk1−/− mice, upon pyrazole plus TNF‐α treatment. Electron microscopy showed altered mitochondrial structure in the jnk2−/− and WT mice, but not the jnk1−/− mice. Conclusions: JNK1 plays a role in the hepatotoxicity, mitochondrial dysfunction, and oxidative stress mediated by pyrazole plus TNF‐α treatment. These findings raise the question as to the potential mechanisms of JNK1 activation related to alcoholic liver injury. (HEPATOLOGY 2011;)