NITRIC-OXIDE IS A MEDIATOR OF THE DECREASE IN CYTOCHROME-P450-DEPENDENT METABOLISM CAUSED BY IMMUNOSTIMULANTS
NITRIC-OXIDE IS A MEDIATOR OF THE DECREASE IN CYTOCHROME-P450-DEPENDENT METABOLISM CAUSED BY IMMUNOSTIMULANTS
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DOI：
10.1073/pnas.90.23.11147
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发表时间：
1993-12-01
影响因子：
11.1
通讯作者：
VANE, JR
中科院分区：
文献类型：
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作者：
KHATSENKO, OG;GROSS, SS;VANE, JR
细菌脂多糖（LPS）和多种其他免疫刺激剂和细胞因子通过降低肝细胞色素P450混合功能氧化酶系统的活性来抑制内源性和外源性物质的代谢。尽管免疫刺激剂的这种作用在近40年前首次被描述，但其机制尚不清楚。现在已知免疫刺激剂通过诱导一氧化氮合酶引起细胞NO过量产生。我们研究了一氧化氮过量是否与LPS抑制肝脏代谢有关。用3- morpholinosydnon亚胺化学分解或一氧化氮合酶产生的NO体外处理肝微粒体，可显著抑制细胞色素p450依赖的氧合反应。在暴露于诱导细胞色素P450不同分子异构体（β -萘黄酮、3-甲基胆蒽和苯巴比妥）的化学物质后，从两种物种（大鼠和鸡）制备的肝微粒体中观察到了NO的这种作用。光谱研究表明，NO在体外与微粒体细胞色素P450中的Fe2+-和Fe3+-血红素发生反应。在体内，LPS降低了大鼠肝微粒体对苯巴比妥诱导的7-己氧基间苯二酚脱烷基作用，并降低了CO结合测量的P450表观含量。这些LPS效应与诱导NO合成有关；lps诱导NO合成与细胞色素P450抑制程度呈正相关。选择性NO合成酶抑制剂N(ω)-硝基- l -精氨酸甲酯在很大程度上阻止了LPS引起的肝微粒体P450活性和CO结合的降低。我们的研究结果表明，一氧化氮的过量产生是介导免疫刺激剂（如LPS）抑制肝脏代谢的主要因素。
Bacterial lipopolysaccharide (LPS) and a diverse array of other immunostimulants and cytokines suppress the metabolism of endogenous and exogenous substances by reducing activity of the hepatic cytochrome P450 mixed-function oxidase system. Although this effect of immunostimulants was first described almost 40 yr ago, the mechanism is obscure. Immunostimulants are now known to cause NO overproduction by cells via induction of nitric oxide synthase. We have investigated whether NO overproduction is involved suppressing hepatic metabolism by LPS. In vitro treatment of hepatic microsomes with NO, produced by chemical decomposition of 3-morpholinosydnonimine or by nitric oxide synthase, substantially suppressed cytochrome P450-dependent oxygenation reactions. This effect of NO was seen with hepatic microsomes prepared from two species (rat and chicken) and after exposure to chemicals that induce distinct molecular isoforms of cytochromes P450 (beta-naphthoflavone, 3-methylcholanthrene, and phenobarbital). Spectral studies indicate that NO reacts in vitro with both Fe2+- and Fe3+-hemes in microsomal cytochromes P450. In vivo, LPS diminished the phenobarbital-induced dealkylation of 7-pentoxyresorufin by rat liver microsomes and reduced the apparent P450 content as measured by CO binding. These LPS effects were associated with induction of NO synthesis; LPS-induced NO synthesis showed a strong positive correlation with the severity of cytochrome P450 inhibition. The decrease in both hepatic microsomal P450 activity and CO binding caused by LPS was largely prevented by the selective NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester. Our findings implicate NO overproduction as a major factor mediating the suppression of hepatic metabolism by immunostimulants such as LPS.