PULMONARY TOXICITY OF SULFUR DIOXIDE AND SULFITE

二氧化硫和亚硫酸盐的肺毒性

• 批准号: 3252012
• 负责人: Gregory Allen Reed
• 金额: $ 6.65万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 1990-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3252012
• 关键词: DNA; benzopyrenes; chemical carcinogen; chromatography; covalent bond; epoxides; hamsters; organ culture; oxidation; respiratory epithelium; sulfites; sulfur oxides; toxin metabolism; trachea neoplasm

Sulfur dioxide and the carcinogenic hydrocarbon benzo(a)pyrene (BP) are ubiquitous air pollutants and are components of tobacco smoke as well. Environmental exposure to these agents is unavoidable and social exposure remains far too prevalent. Epidemiologic data suggest an enhancing effect of sulfur dioxide on the formation of human respiratory tract cancers. Moreover, tumorigenicity studies in rats and hamsters have demonstrated an increased tumor yield and shortened latency period when BP and sulfur dioxide are administered together relative to those animals treated with BP alone. Sulfur dioxide itself is not carcinogenic. One way to enhance the carcinogenicity of BP would be to increase the formation of bay-region diolepoxides, the presumed ultimate carcinogenic derivatives, and to increase covalent modification of DNA by these activated forms of BP. This proposal describes a mechanistic investigation of the role of sulfur dioxide-derived oxidants on the conversion of 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP-7,8-diol) to bay-region diolepoxides, i.e., the final activation step for BP as a carcinogen, and on the formation of specific deoxyribonucleoside adducts. The experimental system will be the intact hamster trachea in short-term organ culture, a model system for BP-induced pulmonary carcinogenesis. Sulfur dioxide exists in aqueous systems at neutral pH as its hydrated, ionized form, the sulfite anion. Spontaneous or enzymatic oxidation of sulfite produces peroxyl radical and peracid derivatives, and these highly reactive oxidants may be involved in the effects of sulfur dioxide on BP carcinogenesis. Sulfite-dependent effects on BP-7,8-diol metabolism will be determined, with particular attention paid to the role of sulfite oxidation products in the process. This project examines a likely target for the expression of sulfur dioxide-induced toxic effects in a mechanistic way. As exposure to sulfur dioxide is unavoidable, such an understanding of the mechanism of toxic action provides the only rational basis for intervention in the toxic process.

二氧化硫和致癌碳氢化合物苯并（A）pyrene（BP）是 无处不在的空气污染物，也是烟草烟雾的成分。 环境暴露这些代理是不可避免的，社会暴露 仍然太普遍了。流行病学数据表明有增强效果 二氧化硫对人呼吸道癌的形成。 此外，大鼠和仓鼠的肿瘤性研究表明 肿瘤产量增加并缩短了BP和硫的潜伏期 相对于用BP处理的动物，二氧化 独自的。 二氧化硫本身不是致癌的。 增强 BP的致癌性是增加海湾的形成 二多氧化物，推测的最终致癌衍生物，以及 通过这些激活形式的BP增加了DNA的共价修饰。 这 提案描述了硫磺作用的机械研究 二氧化衍生的氧化剂关于转化的氧化剂 7,8-二氢7,8-二氢苯并（A）pyrene（BP-7,8-二醇） 双氧化物，即BP作为致癌的最终激活步骤， 关于特定脱氧核苷加合物的形成。 实验 系统将是短期器官文化中完整的仓鼠气管，一个 BP诱导的肺癌发生的模型系统。 二氧化硫 存在于中性pH的水性系统中，作为其水合，电离形式， 亚硫酸盐阴离子。硫酸盐的自发或酶促氧化产生 过氧根本和peracid衍生物，这些高反应性氧化剂 可能参与二氧化硫对BP癌变的影响。 将确定硫酸盐依赖性对BP-7,8-二醇代谢的影响 特别注意亚硫酸盐氧化产物在 过程。该项目研究了表达的可能目标 二氧化硫引起的毒性作用以机械方式。 作为接触 二氧化硫是不可避免的，这样的理解 有毒作用为干预有毒的唯一合理依据 过程。