N-NITROSO COMPOUND DETOXIFICATION

N-亚硝基化合物解毒

• 批准号: 3169623
• 负责人: DAVID E JENSEN
• 金额: $ 14.99万
• 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/3169623
• 关键词: NADPH cytochrome c2 reductase; cellular oncology; chemical carcinogen; chemical carcinogenesis; cimetidine; hamsters; hemoglobin; high performance liquid chromatography; laboratory rat; methylation; methylnitrosourea; nitrosamines; nitroso compounds; nitrosoguanidines; radiotracer; tritium

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性 化合物被认为是来自他们的倾向， 降解成N亚硝基键保持完整的片段。 然而，最近的工作揭示了 这条纽带被瓦解了 这种反硝化作用是一种解毒作用 过程 反硝化作用可能是体内的重要因素， N亚硝基化合物的代谢，并可能 调制优势 我们一直在研究亚硝基胍 (NC)西咪替丁的N-亚硝化衍生物， 被数千万人摄入， 胃溃疡 NC具有相同的N-甲基N亚硝基基团 如致癌物二甲基亚硝胺中所含， 甲基亚硝基脲和1-甲基-2-硝基-1-亚硝基胍。 是 能够在体外甲基化DNA，产生相同的模式 烷基化产物作为致癌物，并给出阳性 在几项短期致癌试验中， 潜力 然而，NC被认为是一个薄弱或 当给予大鼠或小鼠时， 我发现，事实上，NC几乎100%的满意度， 对大鼠或仓鼠给药。 到目前为止，我们已经确定 三个N-亚硝基化活性：谷胱甘肽转移酶， 血红蛋白上的半胱氨酸残基和微粒体活性 细胞色素P450还原酶。 为了帮助我们评估这些活动， 合成一系列 不同2-位取代的1，3-二甲基亚硝基胍 我们预计这将是不同的脆弱性， 脱亚硝化 使用NC，这些类似物和一系列其他类似物可以用于治疗癌症。 我们建议详细说明亚硝基化合物的体外性质， 利用光谱动力学分析的反硝化活性， 色谱反应产物分析。 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 决定其对脱亚硝化敏感性的化合物 活动，并比较这些活动，因为他们调解什么 是一种常见的还原性反硝化反应。 武装 有了对体外化学的理解， 几种化合物，我们将继续我们的工作与大鼠和 仓鼠，希望确定的相对重要性 各种脱氮活动以及它们如何 调制的