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Induction of neuronal nitric oxide synthase (nNOS) in livers of mice treated with toxic doses of acetaminophen
Author(s) -
Agarwal Rakhee,
Banerjee Sudip,
Hinson Jack A
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1106.8
Subject(s) - peroxynitrite , toxicity , chemistry , nitric oxide , acetaminophen , glutathione , nitric oxide synthase , pharmacology , nitrotyrosine , nitration , metabolite , biochemistry , western blot , superoxide , enzyme , biology , organic chemistry , gene
In overdose acetaminophen (APAP) is hepatotoxic. Toxicity occurs by metabolism to a reactive metabolite (NAPQI). Following low doses NAPQI is detoxified by GSH; however, in overdose GSH is depleted and NAPQI covalently binds to proteins. This is followed by oxygen/nitrogen stress (protein nitration) and mitochondrial dysfunction. Nitration is by peroxynitrite formed from nitric oxide and superoxide. Toxicity and nitration in hepatocytes were inhibited by two nNOS inhibitors. In mice the principal nitrated protein was MnSOD. In nNOS knockout mice toxicity was delayed with less nitration compared to wildtype mice. We have now examined livers for the presence of nNOS in APAP toxicity. In livers of saline treated mice nNOS was not observed by Western blot analysis. However, in livers of APAP treated mice nNOS was induced. Low levels of nNOS were detected as early as 2 h following APAP. By 4 h nNOS was significantly induced and by 8 h it was dramatically induced. Its relative induction correlated with relative increases in protein nitration of MnSOD and development of toxicity (serum ALT). As anticipated inducible NOS (iNOS) was also induced following a hepatotoxic dose of APAP but its induction appeared to be later than induction of nNOS. These data indicate that nNOS is induced in livers of APAP treated mice. Supported by NIH grant R01 DK079008.