NEUTROPHIL-MEDIATED NITROSAMINE FORMATION - ROLE OF NITRIC-OXIDE IN RATS
NEUTROPHIL-MEDIATED NITROSAMINE FORMATION - ROLE OF NITRIC-OXIDE IN RATS
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DOI：
10.1016/0016-5085(92)91513-4
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发表时间：
1992-10-01
期刊：
影响因子：
29.4
通讯作者：
YAMADA, T
中科院分区：
文献类型：
--
作者：
GRISHAM, MB;WARE, K;YAMADA, T
众所周知，结肠和直肠的慢性炎症与结直肠癌的风险增加有关，但炎症促进肿瘤形成的机制仍不明确。作者提出，炎性中性粒细胞可能通过精氨酸依赖性氮氧化物（如一氧化氮）的形成产生致癌的亚硝胺。因此，该研究的目的是使用更接近模拟血管外（即，间质）隔室的肠道，并表征亲生物依赖性的N-亚硝基化的模型胺，以产生其亚硝胺衍生物。在没有任何代谢活化的情况下，粘附的炎性中性粒细胞（2 × 106个细胞）在4小时的孵育期内产生12.8 ± 1.4 μmol/L的亚硝酸盐。加入1 mmol/L硝基精氨酸甲酯（l-NAME），不加精氨酸或/和抑制一氧化氮合酶，可抑制35%~ 78%的亚硝酸盐生成，表明亚硝酸盐来源于一氧化氮。相比之下，在相同条件下，循环大鼠中性粒细胞和诱发大鼠巨噬细胞都不产生大量的亚硝酸盐。此外，诱导的中性粒细胞（2 × 106个细胞）能够以与亚硝酸盐产生相似的时间和细胞依赖性模式对2，3-二氨基萘进行N-亚硝基化，产生其亚硝胺衍生物1-萘-2，3-三唑（282 ± 12 nmol/L）。添加各种抗氧化剂（例如，抗坏血酸、还原型谷胱甘肽、α-生育酚类似物）、5-氨基水杨酸、或l-NAME导致80%-85%的对嗜麦芽窄食单胞菌介导的亚硝胺形成的抑制。总之，这些数据表明，炎症中性粒细胞可能是一个重要的代谢来源的内源性致癌物质在时间的活动性肠道炎症。
It is well known that chronic inflammation of the colon and rectum is associated with an increased risk of colorectal cancer, but the mechanisms by which inflammation promotes neoplasia remain undefined. The authors propose that inflammatory neutrophils may produce carcinogenic nitrosamines via thel-arginine-dependent formation of nitrogen oxides such as nitric oxide. Therefore, the objectives of the study were to characterize thel-arginine-dependent formation of nitrogen oxides by inflammatory (elicited) neutrophils using conditions that more closely mimic the extravascular (i.e., interstitial) compartment of the gut and to characterize the neutrophil-dependentN-nitrosation of a model amine to yield its nitrosamine derivative. In the absence of any metabolic activation, adherent, inflammatory neutrophils (2 × 106cells) produced 12.8 ± 1.4 μmol/L of nitrite during a 4-hour incubation period. Omission ofl-arginine and/or inhibition of nitric oxide synthase by the addition of 1 mmol/LNG-nitro-l-arginine methyl ester (l-NAME) resulted in 35%–78% inhibition of nitrite production, suggesting that nitrite was derived from nitric oxide. By comparison, neither circulating rat neutrophils nor elicited rat macrophages produced significant amounts of nitrite under the same conditions. Furthermore, elicited neutrophils (2 × 106cells) were capable ofN-nitrosating 2,3-diaminonapthalene to yield its nitrosamine derivative 1-naptho-2,3-triazole (282 ± 12 nmol/L) in a time- and cell-dependent pattern similar to that of nitrite production. Addition of a variety of antioxidants (e.g., ascorbic acid, reduced glutathione, α-tocopherol analog), 5-aminosalicylic acid, orl-NAME resulted in 80%–85% inhibition of neutrophil-mediated nitrosamine formation. Taken together, these data suggest that inflammatory neutrophils may represent an important metabolic source of endogenous carcinogens during times of active intestinal inflammation.