PULMONARY TOXICITY OF SULFUR DIOXIDE AND SULFITE

二氧化硫和致癌碳氢苯并(A)芘(BP)是 无处不在的空气污染物，也是烟草烟雾的成分。 环境中暴露于这些物质是不可避免的，也是社会暴露。 仍然太普遍了。流行病学数据显示一种增强效应 二氧化硫对人类呼吸道癌症的形成。 此外，对大鼠和仓鼠的致瘤性研究表明， BP和硫磺可增加肿瘤产量和缩短潜伏期 相对于那些用BP治疗的动物，二氧化碳是一起给药的 独自一人。二氧化硫本身并不致癌。一种增强 BP的致癌作用是增加湾区的形成 二环氧化物，被认为是最终的致癌衍生物，以及 增加这些激活形式的BP对DNA的共价修饰。这 该提案描述了硫磺作用的机制研究 二氧化物衍生氧化剂对苯系物转化的影响 7，8-二羟基-7，8-二氢苯并(A)芘(BP-7，8-二醇)至湾区 二环氧化物，即BP作为致癌物的最后活化步骤，以及 关于特定脱氧核糖核苷加合物的形成。实验性的 系统将在短期器官培养中保存完整的仓鼠气管， BP致肺癌模型系统的建立。二氧化硫 以水合、电离形式存在于中性pH的水体系中 亚硫酸盐阴离子。亚硫酸盐的自发氧化或酶促氧化 过氧基和过氧酸衍生物，以及这些高活性氧化剂 可能参与了二氧化硫对BP的致癌作用。 亚硫酸盐依赖对BP-7，8-二醇代谢的影响将被确定， 特别注意亚硫酸盐氧化产物在 这一过程。这个项目检查了一个可能的表达目标 二氧化硫以一种机械性的方式诱导毒性效应。因为暴露于 二氧化硫是在所难免的，这样理解二氧化硫的作用机理 有毒行为是干预有毒行为的唯一合理依据 进程。

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.