Effect of Inhibitors of Nitric Oxide Synthase on Acetaminophen-Induced Hepatotoxicity in Mice

• Published in: Nitric oxide 2002-03, Vol.6 (2), p.160-167
• Main Authors: Hinson, Jack A., Bucci, Thomas J., Irwin, Lisa K., Michael, Sherryll L., Mayeux, Philip R.
• Format: Article
• Language: English
• Subjects: acetaminophen; Acetaminophen - toxicity; Alanine Transaminase - blood; aminoguanidine; Analgesics, Non-Narcotic - toxicity; Animals; Drug Interactions; Enzyme Inhibitors - pharmacology; Guanidines - pharmacology; hepatotoxicity; Liver - cytology; Liver - drug effects; Lysine - analogs & derivatives; Lysine - pharmacology; Male; Mice; NG-Nitroarginine Methyl Ester - pharmacology; nitric oxide; Nitric Oxide - blood; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; nitrotyrosine; omega-N-Methylarginine - pharmacology; peroxynitrite
• ISSN: 1089-8603; 1089-8611
• DOI: 10.1006/niox.2001.0404

We recently reported that following a toxic dose of acetaminophen to mice, tyrosine nitration occurs in the protein of cells that become necrotic. Nitration of tyrosine is by peroxynitrite, a species formed from nitric oxide (NO) and superoxide. In this manuscript we studied the effects of the NO synthase inhibitors N-monomethyl-l-arginine (l-NMMA), N-nitro-l-arginine methyl ester (NAME), l-N-(1-iminoethyl)lysine (l-NIL), and aminoguanidine on acetaminophen hepatotoxicity. Acetaminophen (300 mg/kg) increased serum nitrate/nitrite and alanine aminotransferase (ALT) levels, indicating increased NO synthesis and liver necrosis, respectively. None of the NO synthase inhibitors reduced serum ALT levels. In fact, l-NMMA, l-NIL, and aminoguanidine significantly augmented acetaminophen hepatotoxicity at 4 h. A detailed time course indicated that aminoguanidine (15 mg/kg at 0 h and 15 mg/kg at 2 h) significantly increased serum ALT levels over that for acetaminophen alone at 2 and 4 h; however, at 6 and 8 h serum ALT levels in the two groups were identical. At 2 h following acetaminophen plus aminoguanidine NO synthesis was significantly increased; however, at 4, 6, and 8 h NO synthesis was significantly decreased. Aminoguanidine also decreased acetaminophen-induced nitration of tyrosine. Acetaminophen alone did not induce lipid peroxidation, but acetaminophen plus aminoguanidine significantly increased hepatic lipid peroxidation (malondialdehyde levels) at 2, 4, and 6 h. These data are consistent with NO having a critical role in controlling superoxide-mediated lipid peroxidation in acetaminophen hepatotoxicity. Thus, acetaminophen hepatotoxicity may be mediated by either lipid peroxidation or by peroxynitrite.