Arsenic (As) is a common contaminant in the earth’s crust and widely distributed in food and drinking water. As exposures have been associated with human disease, including cancer, diabetes, lung and cardiovascular disorders, and there is accumulating evidence that early life exposures are important in the etiology. Mode-of-action analysis includes a critical role for metabolic activation of As species to reactive trivalent intermediates that disrupt cellular regulatory systems by covalent binding to thiol groups. The central role of glutathione (GSH) in the chemical reactions of metabolism and disposition of arsenic species was investigated here. The chemical kinetics were measured for reactions in which GSH is a ligand for trivalent As complex formation, a reductant for pentavalent As species, and a participant in ligand exchange reactions with other biological As-thiol complexes. The diverse reactions of GSH with As species demonstrate prominent roles in: (1) metabolic activation via reduction; (2) transport from tissues that are the primary sources of reactive trivalent As intermediates following ingestion (intestine and liver) to downstream target organs (e.g., lung, kidney, and bladder); and (3) oxidation to the terminal metabolite, dimethylarsinic acid (DMA^V), which is excreted. Studies of As metabolism and disposition emphasize the link between metabolic activation vs. excretion of As (i.e., internal dosimetry of reactive species) and the disruption of critical cellular thiol-based regulatory processes that define the dose-response characteristics of disease in human epidemiological studies and animal models and underpin risk assessment.

砷（As）是地壳中的常见污染物，广泛分布于食物和饮用水中。由于暴露已与人类疾病相关，包括癌症，糖尿病，肺和心血管疾病，并且越来越多的证据表明，早期暴露在病因中很重要。作用模式分析包括将As物种代谢活化为反应性三价中间体的关键作用，该中间体通过与硫醇基团的共价结合破坏细胞调节系统。谷胱甘肽（GSH）在砷的代谢和处置的化学反应中的核心作用进行了研究。测量了其中GSH是三价As配合物形成的配体，五价As物种的还原剂的反应的化学动力学，并参与与其他生物As-硫醇复合物的配体交换反应。GSH与As物种的各种反应在以下方面显示出显著作用：（1）通过还原代谢激活；（2）从作为摄入后三价砷作为中间体的主要组织（肠和肝）运输到下游的靶器官（例如，肺，肾和膀胱）；（3）氧化为末端代谢产物二甲基ar酸（DMA^V），将其排出体外。As代谢和处置的研究强调了在人类流行病学研究中，代谢活化与As的排泄（即反应性物种的内部剂量）与关键的基于细胞硫醇的调节过程（定义疾病的剂量反应特征）之间的联系和动物模型，并支持风险评估。