Hemin potentiates nitric oxide-mediated nitrosation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to 2-nitrosoamino-3-methylimidazo[4,5-f]quinoline.
Hemin potentiates nitric oxide-mediated nitrosation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to 2-nitrosoamino-3-methylimidazo[4,5-f]quinoline.
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DOI：
10.1021/tx049792r
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发表时间：
2005-02
影响因子：
4.1
通讯作者：
V. Lakshmi;M. Clapper;Wen‐chi Chang;T. Zenser
中科院分区：
文献类型：
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作者：
V. Lakshmi;M. Clapper;Wen‐chi Chang;T. Zenser
据报道，血红素是结肠内内源性n -亚硝化的重要贡献者，并且随着红肉摄入量的增加，结肠癌的发病率也会增加。本研究以杂环胺2-氨基-3-甲基咪唑[4,5-f]喹啉（IQ）为靶标，评价了hemin增强一氧化氮（NO）介导的亚硝化作用。用高效液相色谱法测定了14c -2-亚硝基氨基-3-甲基咪唑[4,5-f]喹啉（N-NO-IQ）在pH 7.4条件下与NO供体精胺NONOate （1.2 μ m NO/min）在10 μ m IQ条件下的形成情况。一氧化氮自氧化形成的N-NO-IQ达到检测极限（0.1微米），在存在10微米hemin和生成H2O2（葡萄糖氧化酶/葡萄糖）的原位系统时增加了22倍。在1 ~ 10微米血红素范围内，N-NO-IQ形成呈线性增加。NO和H2O2通量分别为0.024和0.25 μ m /min时，亚硝胺形成显著。H2O2超过NO的400倍过量通量或NO超过H2O2的4.8倍过量通量不影响hemin的增强作用。血红素增强产生的活性氮对智商的亲和力是自氧化产生的活性氮的46倍。叠氮化物抑制了自氧化作用，提示与亚硝基铵离子NO+有关。NADH可抑制Hemin的增强，叠氮化物则不能，提示与NO2*或NO2*样物质发生氧化亚硝基化。IQ和2,3-二氨基萘是比仲胺-啉更好的亚硝化靶标。葡聚糖硫酸钠诱导结肠炎的Apc（min）小鼠显示尿亚硝酸盐和硝酸盐水平升高，与iNOS和NO合成表达增加一致。如前所述，相同的条件会增加粪便中的n -亚硝基化合物。因此，血红素增强一氧化氮介导的杂环胺亚硝化提供了一种可测试的机制，通过这种机制，红肉消费可以产生n -亚硝基化合物，并在炎症条件下引发结肠癌，如结肠炎。
Heme has been reported to be an important contributor to endogenous N-nitrosation within the colon and to the enhanced incidence of colon cancer observed with increased intake of red meat. This study uses the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) as a target to evaluate hemin potentiation of nitric oxide (NO)-mediated nitrosation. Formation of 14C-2-nitrosoamino-3-methylimidazo[4,5-f]quinoline (N-NO-IQ) was monitored by HPLC following incubation of 10 microM IQ with the NO donor spermine NONOate (1.2 microM NO/min) at pH 7.4 in the presence or absence of hemin. N-NO-IQ formation due to autoxidation of NO was at the limit of detection (0.1 microM) and increased 22-fold in the presence of 10 microM hemin and an in situ system for generating H2O2 (glucose oxidase/glucose). A linear increase in N-NO-IQ formation was observed from 1 to 10 microM hemin. Significant nitrosamine formation occurred at fluxes of NO and H2O2 as low as 0.024 and 0.25 microM/min, respectively. Potentiation by hemin was not affected by a 400-fold excess flux of H2O2 over NO or a 4.8-fold excess flux of NO over H2O2. Reactive nitrogen species produced by hemin potentiation had a 46-fold greater affinity for IQ than those produced by autoxidation. Azide inhibited autoxidation, suggesting involvement of the nitrosonium ion, NO+. Hemin potentiation was inhibited by NADH, but not azide, suggesting oxidative nitrosylation with NO2* or a NO2*-like species. IQ and 2,3-diaminonaphthylene were much better targets for nitrosation than the secondary amine morpholine. Apc(min) mice with dextran sulfate sodium-induced colitis demonstrated increased levels of urinary nitrite and nitrate consistent with increased expression of iNOS and NO synthesis. As reported previously, identical conditions increased fecal N-nitroso compounds. Thus, hemin potentiation of NO-mediated nitrosation of heterocyclic amines provides a testable mechanism by which red meat consumption can generate N-nitroso compounds and initiate colon cancer under inflammatory conditions, such as colitis.