Hinson Jack A, Bucci Thomas J, Irwin Lisa K, Michael Sherryll L, Mayeux Philip R
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Nitric Oxide. 2002 Mar;6(2):160-7. 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.
我们最近报道，给小鼠服用毒性剂量的对乙酰氨基酚后，坏死细胞的蛋白质中会发生酪氨酸硝化。酪氨酸硝化是由过氧亚硝酸盐引起的，过氧亚硝酸盐是由一氧化氮（NO）和超氧化物形成的一种物质。在本论文中，我们研究了一氧化氮合酶抑制剂N-单甲基-L-精氨酸（L-NMMA）、N-硝基-L-精氨酸甲酯（NAME）、L-N-（1-亚氨基乙基）赖氨酸（L-NIL）和氨基胍对对乙酰氨基酚肝毒性的影响。对乙酰氨基酚（300mg/kg）可提高血清硝酸盐/亚硝酸盐水平和丙氨酸转氨酶（ALT）水平，分别表明一氧化氮合成增加和肝坏死。没有一种一氧化氮合酶抑制剂能降低血清ALT水平。事实上，L-NMMA、L-NIL和氨基胍在4小时时显著增强了对乙酰氨基酚的肝毒性。详细的时间进程表明，氨基胍（0小时时15mg/kg，2小时时15mg/kg）在2小时和4小时时显著提高了血清ALT水平，高于单独使用对乙酰氨基酚时的水平；然而，在6小时和8小时时，两组的血清ALT水平相同。在对乙酰氨基酚加氨基胍处理后2小时，一氧化氮合成显著增加；然而，在4小时、6小时和8小时时，一氧化氮合成显著降低。氨基胍还减少了对乙酰氨基酚诱导的酪氨酸硝化。单独使用对乙酰氨基酚不会诱导脂质过氧化，但对乙酰氨基酚加氨基胍在2小时、4小时和6小时时显著增加了肝脏脂质过氧化（丙二醛水平）。这些数据与一氧化氮在控制对乙酰氨基酚肝毒性中超氧化物介导的脂质过氧化中起关键作用一致。因此，对乙酰氨基酚肝毒性可能由脂质过氧化或过氧亚硝酸盐介导。
