CHEMICAL AND ENZYMIC MECHANISM OF THIOCARBAMIDE TOXICITY

硫代脲毒性的化学和酶机制

• 批准号: 3252710
• 负责人: DANIEL DOERGE
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3252710
• 关键词: DNA; antifungal agents; binding proteins; biotransformation; bone marrow; chemical binding; chemical carcinogenesis; chemical group; chemical models; chemical synthesis; covalent bond; cytochrome P450; cytotoxicity; drug adverse effect; environmental toxicology; enzyme inhibitors; enzyme mechanism; flavins; gas chromatography mass spectrometry; heme; hepatotoxin; high performance liquid chromatography; hyperthyroidism; infrared spectrometry; laboratory rat; nuclear magnetic resonance spectroscopy; nucleic acids; oxidation reduction reaction; oxygenases; peroxidases; radiotracer; scintillation counter; swine; thin layer chromatography; thiourea; thyroid inhibitor; thyroid neoplasm; tissue /cell culture; toxicant interaction; ultraviolet spectrometry

Man is exposed to toxic derivatives of thiourea (thiocarbamides) in the environment from agricultural, industrial and medicinal sources. Since the thyroid gland is the principal target organ for thiocarbamides, the mechanism of inhibition of thyroid peroxidase (TPX) will be determined. Suicide inactivation of TPX will also be defined from the stoichiometry of free and enzyme-bound products which result from inactivation by thiocarbamides. The locus of binding to TPX will be determined by using specifically- radiolabelled inactivators. The catalysis of S-oxygenation reactions by the peroxidase of bone marrow and blood elements, myeloperoxidase, and the hepatic monooxygenases will be investigated since bone marrow and liver toxicity are severe side effects which limit the use of thiocarbamide antithyroid drugs. The production of reactive intermediates from thiocarbamides catalyzed by peroxidases and monooxygenases will be studied by measuring the binding of radiolabelled thiocarbamides to heme, protein and nucleic acid functional groups. Reactive S- oxygenated intermediates from thiocarbamides will be generated in chemical model systems to determine their reactivity with biologically relevant acceptor molecules. This research will correlate the enzymology of thiocarbamide metabolism with the chemistry of putative reactive intermediates to define toxicological mechanisms and health hazards of this significant class of environmental chemicals.

人类接触有毒的硫脲衍生物（硫脲） 在农业、工业和医药环境中 来源。 由于甲状腺是主要靶器官 硫脲类药物抑制甲状腺过氧化物酶的机制 （TPX）将被确定。 TPX 的自杀失活也会 根据游离和酶结合的化学计量来定义 由硫脲灭活产生的产物。 这 与 TPX 的结合位点将通过使用特定的方法来确定 放射性标记的灭活剂。 S-氧化的催化 骨髓和血液成分的过氧化物酶反应， 髓过氧化物酶和肝单加氧酶将 由于骨髓和肝脏毒性很严重，因此进行了研究 限制硫脲类抗甲状腺药物使用的影响。 从硫脲生产反应中间体 过氧化物酶和单加氧酶催化的研究 测量放射性标记的硫脲与血红素的结合， 蛋白质和核酸官能团。 反应性S- 硫脲会产生含氧中间体 在化学模型系统中确定它们的反应性 生物学相关的受体分子。 这项研究将 将硫脲代谢的酶学与 假定的反应中间体的化学定义 这种重要的毒理学机制和健康危害 环境化学品类别。