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Eight hours later, blood was collected and livers were excised. Pathological evaluation showed severe inflammatory responses and necroses only in liver sections from rats in the pyrazole plus LPS group; blood transaminase levels were significantly elevated only in the combination group. Activities of caspase-3 and -9 and positive terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining were highest in the LPS alone and the LPS plus pyrazole group, with no significant difference between the two groups. Lipid peroxidation and protein carbonyls in liver homogenate as well as in situ superoxide production were maximally elevated in the LPS plus pyrazole group. Levels of nitrite plus nitrate and inducible nitric oxide (NO) synthase (iNOS) content were comparably elevated in LPS alone and the LPS plus pyrazole group; however, 3-nitrotyrosine adducts were elevated in the combined group but not the LPS group. It is likely that LPS induction of iNOS, which produces NO, coupled to pyrazole induction of CYP2E1 which produces superoxide, sets up conditions for maximal peroxynitrite formation and production of 3-nitrotyrosine adducts. CYP2E1 activity and content were elevated in the pyrazole and the LPS plus pyrazole groups. Immunohistochemical staining indicated that distribution of CYP2E1 was in agreement with that of necrosis and production of superoxide. These results show that pyrazole treatment enhanced LPS-induced necrosis, not apoptosis. The enhanced liver necrosis appears to involve an increase in oxidative and nitrosative stress generated by the combination of LPS plus elevated CYP2E1 levels.<\/jats:p>","DOI":"10.1152\/ajpgi.00054.2005","type":"journal-article","created":{"date-parts":[[2005,4,22]],"date-time":"2005-04-22T00:34:42Z","timestamp":1114130082000},"page":"G308-G319","source":"Crossref","is-referenced-by-count":53,"title":["Lipopolysaccharide-induced liver injury in rats treated with the CYP2E1 inducer pyrazole"],"prefix":"10.1152","volume":"289","author":[{"given":"Yongke","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur I.","family":"Cederbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(84)05016-3"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2003.50087"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1002\/path.1711520107"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(01)00600-1"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(83)90482-4"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1080\/00365520310007116"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(85)13062-4"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.44.101802.121704"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(01)00741-9"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1099-0461(1999)13:3\/4<127::AID-JBT2>3.0.CO;2-X"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.057174"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.15.1.8679227"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-008X(78)80030-1"},{"key":"R14","unstructured":"Clejan LAand Cederbaum AI.Comparison of the interaction of pyrazole and its metabolite 4-hydroxypyrazole with rat liver microsomes.Drug Metab Dispos18: 393\u2013397, 1990."},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(98)80203-1"},{"key":"R16","doi-asserted-by":"crossref","unstructured":"Davies KJ.Protein damage and degradation by oxygen radicals. 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