{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:08:34Z","timestamp":1772118514091,"version":"3.50.1"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1400,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,11]]},"abstract":"\n \n \n Cytochrome P450 2E1 (CYP2E1) induction and tumor necrosis factor alpha (TNF-\u03b1) production are key risk factors in alcoholic liver injury. Increased oxidative stress from CYP2E1 induction by pyrazole\n in vivo<\/jats:italic>\n sensitizes the liver to TNF-\u03b1-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),\n jnk1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n , and\n jnk2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice were used to identify changes of hepatotoxicity, damage to mitochondria, and production of oxidative stress after pyrazole plus TNF-\u03b1 treatment. Increased serum alanine aminotransferase, inflammatory infiltration, and central necrosis were observed in the\n jnk<\/jats:italic>\n 2\n \u2212\/\u2212<\/jats:sup>\n and WT mice treated with pyrazole plus TNF-\u03b1, but not in the\n jnk1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n 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\n jnk2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n and WT mice, compared to the\n jnk1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice, upon pyrazole plus TNF-\u03b1 treatment, or compared to mice treated with either pyrazole alone or TNF-\u03b1 alone. The antioxidants, catalase, phospholipid hydroperoxide glutathione peroxidase, thioredoxin, and glutathione were lowered, and cytochrome c was released from the mitochondria in the\n jnk2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n and WT mice. Mitochondrial production of superoxide was increased in the\n jnk2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n and WT mice, compared to the\n jnk1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice, upon pyrazole plus TNF-\u03b1 treatment. Electron microscopy showed altered mitochondrial structure in the\n jnk2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n and WT mice, but not the\n jnk1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice.\n Conclusions:<\/jats:italic>\n JNK1 plays a role in the hepatotoxicity, mitochondrial dysfunction, and oxidative stress mediated by pyrazole plus TNF-\u03b1 treatment. These findings raise the question as to the potential mechanisms of JNK1 activation related to alcoholic liver injury. (Hepatology 2011;)\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/hep.24540","type":"journal-article","created":{"date-parts":[[2011,7,11]],"date-time":"2011-07-11T13:32:55Z","timestamp":1310391175000},"page":"1753-1766","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":16,"title":["Hepatotoxicity mediated by pyrazole (cytochrome P450 2E1) plus tumor necrosis factor alpha treatment occurs in c-Jun N-terminal kinase 2\u2212\/\u2212 but not in c-Jun N-terminal kinase 1 \u2212\/\u2212 mice"],"prefix":"10.1097","volume":"54","author":[{"given":"Xiaodong","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Defeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur I.","family":"Cederbaum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-27-20241202","doi-asserted-by":"crossref","first-page":"278290","DOI":"10.1079\/PNS2006496","article-title":"Alcohol, oxidative stress, and free radical damage.","volume":"65","author":"Albano","year":"2006","journal-title":"Proc Nutr Soc"},{"key":"R2-27-20241202","doi-asserted-by":"crossref","first-page":"231242","DOI":"10.1016\/0378-4274(92)90086-Y","article-title":"Ethanol toxicity and oxidative stress.","volume":"63","author":"Bondy","year":"1992","journal-title":"Toxicol Lett"},{"key":"R3-27-20241202","doi-asserted-by":"crossref","first-page":"219240","DOI":"10.1016\/0891-5849(92)90030-K","article-title":"Implication of free radical mechanisms in ethanolinduced cellular injury.","volume":"12","author":"Nordman","year":"1992","journal-title":"Free Rad Biol Med"},{"key":"R4-27-20241202","doi-asserted-by":"crossref","first-page":"585596","DOI":"10.1080\/1071576031000091711","article-title":"A review of the role of reactive oxygen and nitrogen species in alcoholinduced mitochondrial dysfunction.","volume":"37","author":"Bailey","year":"2003","journal-title":"Free Radic Res"},{"key":"R5-27-20241202","doi-asserted-by":"crossref","first-page":"15301537","DOI":"10.1002\/hep.510260621","article-title":"Antibodies to tumor necrosis factor alpha attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat.","volume":"26","author":"Iimuro","year":"1997","journal-title":"Hepatology"},{"key":"R6-27-20241202","doi-asserted-by":"crossref","first-page":"517544","DOI":"10.1152\/physrev.1997.77.2.517","article-title":"Cytochrome P4502E1: its physiological and pathological role.","volume":"77","author":"Lieber","year":"1997","journal-title":"Physiol Rev"},{"key":"R7-27-20241202","first-page":"G605G611","article-title":"Mechanisms of hepatic toxicity. 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