LUNG METABOLISM & TOXICITY OF ENVIRONMENTAL ARSENICALS

砷（As）是一种重要的环境毒素，对人体有毒害作用 然而，吸入暴露后， 无机砷和肺部尚未进行任何详细检查。 在 此外，评估砷诱发肺癌的风险 一般忽略AS（III）和As（V）之间的任何毒性差异， 事实上，这些砷物种被认为是通过不同的 毒性机制 这一点很重要，因为对致癌物质的估计 潜在的是基于冶炼厂接触AS（三）化合物，而作为 空气中的砷主要由五价砷组成。 我们的具体 目的是确定是否砷化合物， 氧化态和物理态也在它们的毒性方面不同， 肺和特定的肺细胞群。 这包括 研究肺细胞如何保护自己免受有毒物质的侵害 砷剂的影响，特别是其结合和/或 代谢砷化合物以调节细胞毒性。 最近 信息表明，通过硫醇，特别是谷胱甘肽， 在砷化合物的代谢和结合中很重要， 这种减少可能是一个重要的生物活化步骤的毒性， 砷剂。 具体目标包括研究肺部对可溶性钠的作用 砷酸盐（V）和亚砷酸钠（III）。 代谢作用包括 氧化、还原和甲基化将被定量。 另外还有按 As（III）、As（V）及其甲基化代谢产物的毒性研究 （甲基胂酸（MMA）和二甲基胂酸（DMA）） 将测定肺和特定的肺细胞群。 这将 包括丙酮酸脱氢酶、谷胱甘肽水平 代谢、胶原蛋白合成和降解、DNA链断裂和 肺组织和细胞结构的修复和改变。 最后， 微溶形式的AS（III）和As（V）对 将确定肺中的代谢和毒性，以评估 吞噬细胞参与砷的肺毒性。

Arsenic (As) is an important environmental toxin which is toxic to the lung after inhalation exposure, however, the interaction between inorganic arsenic and the lung has not been examined in any detail. In addition, assessments of the risk from arsenic-induced lung cancer generally ignore any toxic differences between AS(III) and As(V) despite the fact that these arsenic species are assumed to act by different toxic mechanisms. This is important since estimates of the carcinogenic potential are based on smelter exposures to AS(III) compounds whereas As levels in the air are primarily composed of As(V). Our specific objective is to determine if arsenical compounds which differ in oxidation state and physical state also differ in their toxicity toward the lung and toward specific lung cell populations. This includes an investigation of how the lung cells protect themselves from the toxic effects of arsenicals, particularly in their ability to bind and/or metabolize arsenical compounds to modulate cellular toxicity. Recent information suggests that reduction by thiols, particularly glutathione, is important in the metabolism and binding of arsenical compounds and that reduction may be an important bioactivation step in the toxicity of the arsenicals. Specific aims include a study of the lung action on soluble sodium arsenate (V) and sodium arsenite (III). The metabolic actions including oxidation, reduction and methylation will be quantified. In addition, a study of the toxicity of As(III), As(V) and its methylated metabolites (monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)) on whole lung and specific lung cell populations will be determined. This will include changes in pyruvate dehydrogenase, glutathione levels and metabolism, collagen synthesis and degradation, DNA strand breaks and repair and alterations of lung tissue and cellular structure. Finally, the effect of slightly soluble forms of AS(III) and As(V) on the metabolism and toxicity in the lung will be determined to assess the involvement of phagocytic cells in the pulmonary toxicity of arsenic.