The Human Genetics of Arsenic Biotra

砷 Biotra 的人类遗传学

• 批准号: 6901470
• 负责人: H VASKEN APOSHIAN
• 金额: $ 38.89万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901470
• 关键词: arsenic; biotransformation; clinical research; environmental contamination; environmental health; environmental toxicology; enzyme activity; enzyme mechanism; epidemiology; genetics; glutathione; hazardous substances; human subject; metal metabolism; tissue /cell culture; toxin metabolism

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.

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会产生几种化学形式的砷，其毒理学效力差异很大。因此，有理由认为人体对砷的生物转化是其毒性作用的关键。砷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，一些研究表明，包括尿砷代谢物水平家族聚集的报告。因此，了解砷的代谢是了解其对人体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参与砷的生物转化