N-NITROSO COMPOUND DETOXIFICATION

N-亚硝基化合物解毒

• 批准号: 3169616
• 负责人: DAVID E JENSEN
• 金额: $ 15.95万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-02-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3169616
• 关键词: NADPH cytochrome c2 reductase; WI38 cell; blood chemistry; cell population study; cellular oncology; chemical carcinogen; chemical carcinogenesis; cimetidine; hemoglobin; high performance liquid chromatography; methylation; nitrosamines; nitroso compounds; nitrosoguanidines; radiotracer; tritium; urinalysis

The cytotoxic and carcinogenic potential of alkylating Nnitroso compounds is thought to be derived from their propensity to degrade to fragments in which the Nnitroso bond remains intact. Recent work, however, has revealed degradation pathways in which this bond is dissolved. This denitrosation is a detoxification process. Denitrosation could be a significant factor in the in vivo metabolism of Nnitroso compounds and potentially could be modulated advantage. We have been studying nitrosocimetidine (NC), the N-nitrosated derivative of cimetidine (Tagamet), a drug ingested by tens of millions of people for the treatment of stomach ulcers. NC has the same N-methylNnitroso grouping as contained in the carcinagens dimethylnitrosamine, methylnitrosourea and 1methyl-2-nitro-1-nitrosoguanidine. It is capable of methylating DNA in vitro, generating the same pattern of alkylation products as the noted carcinagens, and gives positive indications in the several shortterm tests for carcinogenic potential. However NC has been judged to be a weak or noncarcinagen when administered to rats or mice and we have found that, in fact, NC is nearly 100 percent denitorsated upon administration to rats or hamsters. We have thus far identified three NCdenitrosating activities: glutathione transferase, the cysteine residues on hemoglobin and a microsomal activity tentatively identified as NADPHcytochrome P450 reductase. As an aid in our evaluation of these activities we are in the process of synthesizing a series of 1,3dimethyl1nitrosoguanidines variously 2-position substituted which we anticipate will be differentially vulnerable to denitrosation. Using NC, these analogues and a range of other Nnitroso compounds we propose to detail the in vitro properties of the denitrosating activities using spectral kinetic analysis and chromatographic reaction product analysis. We will also identify and evaluate inhibitors and enhancers of these activities. Our aim will be to elucidate the chemical properties of N-nitroso compounds which dictate their susceptibility to denitrosating activities and to compare these activities as they mediate what we sense is a common reductive denitrosation reaction. Armed with this understanding of the in vitro chemistry and with our several compounds we will continue our work with rats and hamsters with the hope of determining the relative importance of the various denitroasating activities and how they might be modulated.

烷基化亚硝基的细胞毒性和致癌作用 化合物被认为是由其倾向于 降解成碎片，其中的亚硝酸键保持完整。 然而，最近的研究揭示了 而这个纽带已经解开了。这种脱氮作用是一种解毒作用 进程。反硝化作用可能是体内的一个重要因素。 亚硝基化合物的代谢和潜在的 调制优势。我们一直在研究亚硝咪替丁 西咪替丁(泰格美)的N-亚硝化衍生物(NC) 被数千万人摄取用于治疗 胃溃疡。NC具有相同的N-甲基亚硝基 在致癌物质二甲基亚硝胺中， 甲基亚硝脲和1甲基-2-硝基-1-亚硝胺。它是 能够在体外甲基化DNA，产生相同的模式 烷基化产物作为已知的致癌物，并给出阳性结果 几种短期致癌试验的适应症 潜力。然而，NC已被判断为弱或 当给大鼠或小鼠服用非致癌药物时，我们有 发现，事实上，NC几乎100%脱氮 对老鼠或仓鼠的管理。到目前为止，我们已经确定 三种NC反硝化活性：谷胱甘肽转移酶， 半胱氨酸残基对血红蛋白和微粒体活性的影响 初步鉴定为NADPH细胞色素P450还原酶。 为了帮助我们对这些活动进行评估，我们在 合成一系列的过程 不同2位取代的1，3-二甲基-1-亚硝基 我们预计它会受到不同程度的攻击 反硝化。使用NC，这些类似物和一系列其他 我们建议详细介绍亚硝基化合物的体外性质 对脱氮活性的光谱动力学分析和 层析反应产物分析。我们还将确定 并评估这些活性的抑制剂和增强剂。我们的目标 将阐明N-亚硝基的化学性质 决定其对反硝化反应敏感性的化合物 活动，并将这些活动进行比较，因为它们调解 我们感觉是一种常见的还原脱氮反应。武装的 有了对体外化学的了解和我们的 几种化合物我们将继续我们对老鼠和 仓鼠，希望确定它们的相对重要性 各种脱氮活动及其可能的方式 调制过的。