Arsenic toxicology: Five questions

We have tried to address five questions dealing with five of the arms of arsenic toxicology: biotransformation, ROS, polymorphism, treatment, and protein binding. The first question, "What enzyme is responsible for the methylation of arsenic species in the human?", still needs further investigative effort to obtain an answer. The dilemma continues. For CYT 19 to be accepted as the methylation enzyme of humans, purification of the protein and its activity from surgically removed human tissue is required. This has not been accomplished for either CYT 19 or the rabbit methyltransferase. Second, the conventional belief that arsenite inhibits PDH and perhaps other dithiol-containing enzymes by chelating the thiol groups now needs to be expanded to include ROS. The latter also can be generated as an inhibitory agent by arsenicals. Third, a number of polymorphisms in human GST ωs, CYT 19, and PNP have been reported. Two studies have linked these polymorphisms with changes in urinary arsenic species. There has been a minimum of investigations dealing with both studies of polymorphisms of human genes known to be involved in arsenic metabolism and the determinations of all of the possible urinary arsenic species, especially MMA(III) and DMA(III). In fact, the genetics of arsenic toxicity is a barren field at present. Fourth, DMSA and DMPS are effective in mobilizing the excretion of arsenic from the human. DMPS seems to be more consistently effective in the clinical improvement of individuals chronically exposed to arsenic. With the millions of people now known to be consuming toxic amounts of arsenic in their drinking water or food, a large-scale clinical trial of arsenic antidotes is needed and recommended so that when remediation of arsenic exposure is finally accomplished, arsenic body burdens of exposed humans can be decreased safely. Fifth, with new proteomic techniques available, such as DIGE, research in arsenic toxicology now may be expanded to acquire more specific knowledge as to the exact role of specific proteins in arsenic intoxication and detoxication. Using two-dimensional electrophoresis procedures in which protein extracts from two subjects can be electrophoresed together by using two fluorescent dyes followed by MS of protein spots may quicken the understanding of the role of proteins in arsenic metabolism. A recent study clearly has shown that the differences in the number of cysteine residues in human and mouse hemoglobin are responsible for the greater accumulation of arsenic species in rat blood. While a number of recent papers have been emphasized in this review, the need for confirmation of their conclusions by other investigators is needed. The importance of their results at this time, however, should not be minimized. Rather, they should stimulate investigators to reexamine and expand their thinking and investigations and, hopefully, attract new investigators.