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GENETIC FACTORS IN THE METABOLISM AND TOXICITY OF ARSENIC
Impact/Purpose:
To understand the role of enzymatically-catalyzed methylation of arsenic in the action of this metalloid as a toxin and carcinogen.
Description:
As noted in the 1999 NRC report on arsenic in drinking water understanding variability in the metabolism of inorganic arsenic in humans is critical to understanding the response of humans to chronic exposure to this metalloid. Interindividual variation in capacity to produce the methylated metabolites of inorganic arsenic has been attributed to differences in ethnicity, age, sex, nutritional status, and intercurrent disease. There is considerable interindividual variation in the occurrence of specific signs and symptoms of chronic arsenic intoxication. For example, a relatively small fraction of individuals chronically exposed to inorganic arsenic in drinking water develop blackfoot disease, a progressive occlusive disorder of the peripheral vasculature. Studies in chronically-exposed populations find absolute or relative increases in the amount of methylated arsenic in urine to be associated with increased occurrences of arsenic-induced skin lesions, suggesting a role for metabolic capacity in determination of susceptibility. Because the methylated metabolite of inorganic arsenic are potent cytotoxins, genotoxins, and enzyme inhibitors, elucidating the pathway for arsenic methylation is critical to assessing risk associated with exposure to inorganic arsenic. The proposed research is based on three postulates. First, that interindividual variation in response reflects the kinetic properties of the enzymes that catalyze the reduction and methylation of arsenicals. Second, that the kinetic properties of these enzymes are determined by their primary sequences (hence, by the genotypes for these proteins). Third, that control of the expression of these genes may determine the capacity for metabolism of arsenic. As a corollary, we suggest that genotypes for these enzymes are causally linked to disease susceptibility phenotypes. Thus, polymorphisms in these genes that determine their catalytic activities and that the transcriptional regulation will be reflected in different capacities for the metabolism of inorganic arsenic and, ultimately, to the development of the adverse health effects. Such studies are relevant to predicting the hazard associated with chronic exposure to this metalloid. This laboratory has identified and cloned Cyt19, a gene encoding the human arsenic methyltransferase. In the proposed research, we will examine the relationship between the genotype and expression of its protein product and the phenotype for the capacity to methylate inorganic arsenic in human cells and in individuals who chronically exposed to iAs. Initially we will examine in cultured primary human hepatocytes, the relation between the Cyt19 genotype and the phenotype for the metabolism of As as reflected by the amounts of inorganic arsenic and its methylated metabolites in cells and media. To estimate the extent of variability in the genotype and expression of Cyt19, we will extend this research to examine genotypic variation in Cyt19 using DNA isolated from peripheral blood of a number of human volunteers. Finally we will examine the relation between the Cyt19 genotype and the phenotype for the metabolism of As as reflected by the amounts of inorganic arsenic and its methylated metabolites in blood and urine from humans chronically exposed to iAs in drinking water.
An understanding of the role of genetic susceptibility in the control of arsenic metabolism will benefit the risk assessment process by identifying subpopulations of individuals who are genetically predisposed to greater susceptibility to the toxic or carcinogenic effects of chronic arsenic exposure. Quantitative data on the contribution of genotype to the capacity to methylate inorganic arsenic identified in the proposed research as modifiers of the metabolism and toxicity of arsenic can be incorporated into quantitative models which describe the systemic and cellular metabolism of inorganic arsenic and its mode(s) of action as a toxin and carcinogen. These quantitative estimates of the variation in metabolic capacity as a source of interindividual variability can be incorporated into a quantitative dose-response model. Understanding the role of genetically determined capacity to metabolize inorganic may also be used to identify susceptible individuals and populations for special consideration in the risk assessment and management processes.