REACTIVE INTERMEDIATES IN TOXICANT ACTION

具有毒性作用的反应中间体

基本信息

批准号：
3253048
负责人：
JOHN E CASIDA
金额：
$ 23.39万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-09-19 至 1993-08-31
项目状态：
已结题

项目摘要

Reactive intermediates are involved in the action of many toxicants. Detailed knowledge of the nature of those derived from pesticides (with their broad range of chemical structures and biological activities and inevitable exposure of humans) is particularly important so that any toxicological hazards can be anticipated. In this research, relationships between chemical reactivity and biological activity are evaluated at primary target sites and in relation to conjugate formation and derivatization of DNA and proteins. Reactive intermediates are identified in model chemical and photochemical systems, in enzyme preparations (e.g., cytochrome P-450- and FAD-dependent microsomal oxidases and gluthathione (GSH) S-transferases) and in rats and mice. 13C-Enriched compounds and 1H-13C correlated two-dimensional NMR spectroscopy are used to examine directly reactive intermediates in relevant systems which are also analyzed by GC-MS. The research concentrates on four types of pesticides, which are potential environmental contaminants with possible direct or derived mutagenic or carcinogenic activity. First, since diallate and its analogs are microsomally-oxidized to strongly mutagenic 2-halopropenals and ethylene dibromide gives thiiranium ions by GSH conjugation, the significance and balance of comparable processes are examined with 1,2-dibromo-3-chloropropane via 2- bromopropenal and bromochloroacetone as metabolic intermediates. Second, nitrofen is metabolically and photochemically reduced via mutagenic and highly reactive hydroxylamino and nitroso derivatives, the latter reacting with bioolefins to give nitroxide radicals. Therefore potential hazards from such products formed from other nitrodiphenyl ethers and chlordimeform and of imines from glyphosate are assessed. Third, the carcinogenic activity of alachlor may be associated with metabolic activation of the N-methoxymethyl substituent or with formation of reactive chloroacetanilide, benzoiminoquinone or nitroso/hydroxylamino metabolites; the former is the more likely from present work also concerned with N-methyl activation of other chloroacetanilides, daminozide and hexamethylphosphoramidate. Finally, tetrahaloalkanes (e.g., tralomethrin, dibrom and a dicofol impurity) undergo metabolic and photochemical activation to potentially toxic dihaloalkenes. Because some alkenes (e.g., methfuroxam and an allethrin photoproduct) undergo further epoxidation, a specific aim is to define the substituents and reactions that may create toxicological problems in formation and further activation of alkenes. The overall objectives are to recognize potentially hazardous compounds and to propose structural modifications to maximize the benefits and minimize the risks in pesticide use.

反应中间体参与许多作用有毒物质。衍生的性质的详细知识来自农药（具有广泛的化学结构和生物活动以及人类不可避免的暴露）是特别重要的是，任何毒理学危害都可以预期的。在这项研究中，化学之间的关系在主要目标上评估反应性和生物活性位点以及与缀合物形成和衍生化有关 DNA 和蛋白质。反应中间体被鉴定为酶中的化学和光化学系统模型制剂（例如细胞色素 P-450 和 FAD 依赖性微粒体氧化酶和谷胱甘肽 (GSH) S-转移酶）和在大鼠和小鼠中。 13C 富集化合物和 1H-13C 相关二维核磁共振波谱用于检查相关系统中的直接反应中间体也通过 GC-MS 进行分析。该研究集中于四种类型的农药，它们是潜在的环境污染物可能直接或衍生的致突变或致癌活性。首先，由于拨号及其类似物被微粒体氧化成强诱变性 2-卤代丙烯醛和二溴乙烷通过以下方式生成硫钛离子 GSH结合、可比较的意义和平衡使用 1,2-二溴-3-氯丙烷通过 2- 溴丙烯醛和溴氯丙酮作为代谢物中间体。其次，除草醚具有代谢作用，通过诱变和高反应性进行光化学还原羟氨基和亚硝基衍生物，后者与生物烯烃产生硝基氧自由基。因此存在潜在危险由其他硝基二苯醚形成的此类产品和评估了杀虫脒和草甘膦中的亚胺。三、甲草胺的致癌活性可能与 N-甲氧基甲基取代基的代谢活化或形成反应性氯乙酰苯胺，苯并亚氨基醌或亚硝基/羟氨基代谢物；这从目前的工作来看，前者更有可能也涉及其他氯代乙酰苯胺、丁酰肼和苯酰肼的 N-甲基活化六甲基氨基磷酸酯。最后，四卤代烷烃（例如，曲洛菊酯、二溴和三氯杀螨醇杂质）经过代谢以及光化学活化潜在有毒的二卤代烯烃。因为某些烯烃（例如甲呋沙姆和丙烯菊酯）光产物）进一步环氧化，具体目标是定义可能产生的取代基和反应形成和进一步激活的毒理学问题烯烃。总体目标是认识到潜在的危险化合物并提出结构修改最大化农药使用的效益并最小化农药使用的风险。