Newer Developments in Arsenic Toxicity

Abstract

There have been a number of new and exciting advances in the understanding of arsenic toxicity. Organic trivalent arsenicals have been the drug of choice in the treatment of African trypanosomes, the cause of sleeping sickness. In the past, various mechanisms have been proposed for their mode of action in the treatment of this parasitic disease. It now appears that these arsenicals form an adduct with N1,-N8(glutathionyl)spermidine which inhibits trypanothione disulfide reductase. This enzyme in conjunction with a nonenzymatic reaction is responsible for the maintenance of the required intracellular levels of GSH and perhaps other thiols in African trypanosomes. The primary targets of As3+ in mammalian systems are pyruvate dehydrogenase, thiolase, and glutathione reductase. Even though it appears that pyruvate dehydrogenase is the most sensitive target, the net result of these inhibitions is a decreased gluconeogenesis that should be taken into account when treating arsenic poisoning. Although these advances have been made in the understanding of arsenic toxicity, virtually no progress has been made in understanding the biochemical mechanism of action of arsine, probably the deadliest of all arsenic compounds. This lack of progress is disappointing as well as worrisome since arsine is one of the important starting materials in the newer high tech industries. There have been, however, advances made in the treatment of arsenic toxicity. Meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-l-sulfonic acid are orally effective, dithiol chelating agents useful for treating arsenic poisoning. DMSA is an orphan drug for which a New Drug Application has been filed.