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

CYP2E1 induction and 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 activation of c-jun N-terminal kinase (JNK) and mitochondrial damage. The goal 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 following pyrazole plus TNF-α treatment. Increased serum ALT, 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, GPx-4, 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 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.