ENVIRONMENTAL HYDRAZINES AND METHYLATION OF DNA GUANINE

肼是一种具有肝毒性和神经毒性的环境污染物 和弱肝癌。 中毒剂量的肼的施用 对啮齿类动物的结果形成7-甲基鸟嘌呤和O 6-甲基鸟嘌呤， 靶器官DNA 提出了肼和肼生成 衍生物是致癌的，因为肼与内源性 甲醛形成四甲酰基三嗪和/或甲醛嗪， 被代谢成甲基化试剂。 对环境具有重要意义的肼基 将在体内测试化合物诱导甲基化的能力， DNA鸟嘌呤及其释放肼作为游离碱的能力;马来酸 酰肼，3-氨基-1，2，4-三唑，甲基甲酰基肼， 2-羟乙基肼，异丙肼，异羧肼，烟酰胺，苯乙肼， 磺胺甲咪唑，磺胺甲氧哒嗪，磺胺苯吡唑，呋喃唑酮， 呋喃妥因，呋喃西林，异烟肼，肼苯哒嗪，乙酰唑胺，和 将苯肼经口给予Sprague道利大鼠。 肼甲酰胺、肼基组氨酸、甲醛嗪和 还将测试四甲酰基三嗪。 二十四小时后 甲基鸟嘌呤将从中性热分析和 肝、肾和肺DNA的温和酸水解产物， 高效液相色谱荧光法 分光光度检测 肼将通过hplc测量为 从组织的酸提取物中提取的酞肼。 形成偶氮甲烷， 将测定氧化偶氮甲烷、甲基偶氮甲醇和甲基偶氮甲醇 在体外和体内啮齿动物系统中通过HPLC作为 说明肼活化为 甲基化剂 缩合产物的形成动力学 肼和甲醛将在体内和体外啮齿动物中进行研究 特别注意酒精的作用， 醛脱氢酶在这些产物的代谢活化中的作用。 DNA 通过单甲基肼-甲醛缩合产物进行甲基化， 将测定1，4-二甲基六氢-1，2，4，5-四嗪。 环境 甲醛和肝毒素（二甲基亚硝胺， 二乙基亚硝胺，四氯化碳和磷）将进行研究 因为它们能够提高组织中的甲醛含量 肼诱导的DNA鸟嘌呤甲基化。 甲醛会 通过HPLC测定。 肼诱导的甲基化对 5-甲基胞嘧啶在DNA中的分布和对维持 将研究新生大鼠和部分肝切除大鼠的肝脏; 5-甲基胞嘧啶将从DNA的酶水解产物中测定， 高效液相色谱法 拟议的研究将提供实验证据，以评估 环境肼化合物作为潜在的DNA损伤剂， 它们可能对人类健康造成致癌危害。

Hydrazine is an environmental contaminant which is hepato- and neurotoxic and weakly hepatocarcinogenic. Administration of toxic doses of hydrazine to rodents results in formation of 7-methylguanine and O6-methylguanine in target organ DNA. It is proposed that hydrazine and hydrazine-generating derivatives are carcinogenic because hydrazine reacts with endogenous formaldehyde to form tetraformyltrisazine and/or formalazine which in turn are metabolized to methylation agents. Environmentally important hydrazino compounds will be tested in vivo for their ability to induce methylation of DNA guanine and their ability to release hydrazine as the free base; maleic hydrazide, 3-amino-1,2,4-triazole, methylformylhydrazine, 2-hydroxyethylhydrazine, iproniazid, isocarboxazid, nialamide, phenelzine, sulfamethizole, sulfamethoxypyridazine, sulfaphenazole, furazolidone, nitrofurantoin, nitrofurazone, isoniazid, hydralazine, acetazolamide, and phenylhydrazine will be administered orally to Sprague Dawley rats. Hydrazinecarboxamide, hydrazinohistidine, formalazine, and tetraformyltrisazine will also be tested. Twenty-four hours later methylguanines will be quantitatively determined from neutral thermal and mild acid hydrolysates of liver, kidney, and lung DNA fractionated by high performance liquid chromatography (hlpc) with fluorescence spectrophotometric detection. Hydrazine will be measured by hplc as phthalhydrazine from acid extracts of tissue. Formation of azomethane, azoxymethane, methylazomethanol and methylazoxymethanol will be determined by hplc in in vitro and in vivo rodent systems as an initial step in the elucidation of biochemical pathways for the activation of hydrazine to a methylating agent. Kinetics of formation of condensation products of hydrazine and formaldehyde will be studied in in vivo and in vitro rodent systems, with particular attention given to the role of alcohol and aldehyde dehydrogenases in the metabolic activation of these products. DNA methylation by the monomethylhydrazine-formaldehyde condensation product, 1,4-dimethylhexahydro-1,2,4,5-tetrazine, will be determined. Environmental sources of formaldehyde and the hepatotoxins (dimethylnitrosamine, diethylnitrosamine, carbon tetrachloride, and phosphorus) will be studied for their ability to raise tissue formaldehyde levels and augment hydrazine-induced methylation of DNA guanine. Formaldehyde will be measured by hplc. The effect of hydrazine-induced methylation on the distribution of 5-methylcytosine in DNA and on maintenance methylation in liver of newborn and partially hepatectomized rats will be investigated; 5-methylcytosine will be determined from enzymic hydrolysates of DNA by hplc. The proposed studies will provide experimental evidence to evaluate environmental hydrazine compounds as potential DNA damaging agents and the carcinogenic hazard they may present to human health.