The Human Genetics of Arsenic Biotra

流行病学研究证实无机砷是一种人类致癌物。很明显，砷的复杂生物转化途径产生了几种化学形式的砷，其毒理学效力差异很大。因此，可以合理地预期，人体对砷的生物转化是其毒性作用的关键。砷的生物转化似乎具有相当程度的个体间变异性，具有遗传决定的特征，这是由一些研究提出的，包括尿砷代谢物水平的家族聚集性报告。因此，了解砷的代谢是了解其对人类毒理学影响的先决条件。该项目将充分表征所有已知基因的遗传变异性，涉及砷的生物转化， 在全球范围内收集的不同种族的砷暴露个体样本。在这些人群中，我们将进行我们认为是迄今为止最大的遗传关联研究，其目的是将砷代谢的个体差异与参与砷代谢的候选基因（包括GSTO 1 -1、PNP和CYT 19）的DNA序列差异（以两种互补方式-酶活性和尿代谢物水平测量）联系起来。后续目标将针对表达候选基因产物的变体同种型并表征其生化活性，以补充具有机制信息的遗传关联。最后，该项目将继续该小组过去的成功，努力确定新的砷生物转化途径成员。成功 这项工作的完成将提供一个最全面的数据集，描述人类生物转化的砷，并将是一个宝贵的资源，科学界，以及一般社区的利益相关者在SBRP计划。

Epidemiological studies have confirmed that inorganic arsenic is a human carcinogen. It is clear that the complex biotransformation pathways of arsenic undergoes produces several chemical forms of arsenic that vary greatly in their toxicological potency. Thus, it is reasonable to expect that human biotransformation of arsenic is key to its toxic effects. Arsenic biotransformation appears to have a considerable degree of inter-individual variability that has the characteristics of being heritably determined, suggested by a number of studies, including reports of familial aggregation of urinary arsenic metabolite levels. Thus, understanding the metabolism of arsenic is a prerequisite to understanding its toxicological effects in humans. This project will fully characterize the genetic variability of all known genes involved in arsenic biotransformation in a diverse group of ethnically defined, globally collected human samples of arsenic-exposed individuals. Within these populations we will conduct what we believe to be the largest genetic association study to date, with the aim of relating individual variation in arsenic metabolism, measured in two complementary ways-enzymatic activity and urinary metabolite levels, to variations in the DNA sequence of candidate genes involved in arsenic metabolism, including GSTO1-1, PNP, and CYT19. Subsequent Aims will be directed at expressing variant isoforms of candidate gene products and characterizing their biochemical activity to complement the genetic associations with mechanistic information. Finally, this project will continue the group's past success in efforts to identify new arsenic biotransformation pathway members. The successful completion of this work will provide one of the most comprehensive data sets describing the human biotransformation of arsenic, and will be a valuable resource to the scientific community, as well as the general community of stakeholders in the SBRP program.