DSMA and DMPS are chelating agents that are effective for treating heavy metal intoxication in humans. DMSA, an orphan drug, was approved by the U.S. FDA in January 1991 for treating childhood lead poisoning and is expected to be the drug of choice for this. DMPS has been approved by the German FDA as a mercury antidote. Highly sensitive and selective analytical assays involving bimane derivatization, HPLC, and fluorescence detection have been developed in this lab and have resulted in the safe analytical determination, in humans, of these chelating agents and their metabolites. The more knowledge available about any drug, the better and safer therapeutic use can be made of it. After oral administration to humans, DMSA appears to be transported to the kidney by plasma albumin where it appears to be biotransformed to DMSA-cysteine mixed disulfides. This brings up the question as to whether chelation only takes place in the kidney - a question that will be investigated. There appears to be a major species difference in the biotransformation of DMSA. Mice, rats, and rabbits do not metabolize DMSA to the DMSA-cysteine mixed disulfide. The biotransformation of DMSA will continue to be elucidated in humans and that for DMPS will begin. The DMPS metal chelates of divalent Pb, Hg, Cd, and Ni will be synthesized and their structures determined. Metal chelates of DMPS and DMSA will be isolated from the urine and their structures determined. The redox potentials of DMSA and DMPS will be determined. Preliminary results indicate a DMPS challenge test to detect """"""""mini-exposure"""""""" to mercury is promising. This is an interdisciplinary investigation in which a molecular and cellular biologist/pharmacologist, a chemist, and a physician will interact to gain basic and applied information, very often in humans, about these chelating agents. The long-term goal is to study the toxicological and pharmacological properties of these orally effective therapeutic agents so that safe chelating agents will be available for human therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES003356-09
Application #
3250590
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1984-05-01
Project End
1995-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Arts and Sciences
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Fang, X; Hua, F; Fernando, Q (1996) Comparison of rac- and meso-2,3-dimercaptosuccinic acids for chelation of mercury and cadmium using chemical speciation models. Chem Res Toxicol 9:284-90
Fang, X; Fernando, Q (1995) Stereoisomeric selectivity of 2,3-dimercaptosuccinic acids in chelation therapy for lead poisoning. Chem Res Toxicol 8:525-36
Fang, X; Fernando, Q (1994) Conformations of zinc chelates of meso- and rac-2,3-dimercaptosuccinic acid in aqueous solution. Chem Res Toxicol 7:882-90
Fang, X; Fernando, Q (1994) A comparative study of meso- and rac-2,3-dimercaptosuccinic acids and their zinc complexes in aqueous solution. Chem Res Toxicol 7:770-8
Hurlbut, K M; Maiorino, R M; Mayersohn, M et al. (1994) Determination and metabolism of dithiol chelating agents. XVI: Pharmacokinetics of 2,3-dimercapto-1-propanesulfonate after intravenous administration to human volunteers. J Pharmacol Exp Ther 268:662-8
Fang, X; Fernando, Q (1994) Synthesis, structure, and properties of rac-2,3-dimercaptosuccinic acid, a potentially useful chelating agent for toxic metals. Chem Res Toxicol 7:148-56
Aposhian, H V; Levine, D J; Rivera, M et al. (1993) Determination and metabolism of dithiol chelating agents: the zinc chelate of the dimethyl ester of meso-2,3-dimercaptosuccinic acid increase biliary excretion of cadmium and platinum. Chem Res Toxicol 6:208-14
Maiorino, R M; Aposhian, M M; Xu, Z F et al. (1993) Determination and metabolism of dithiol chelating agents. XV. The meso-2,3-dimercaptosuccinic acid-cysteine (1:2) mixed disulfide, a major urinary metabolite of DMSA in the human, increases the urinary excretion of lead in the rat. J Pharmacol Exp Ther 267:1221-6
Aposhian, H V; Maiorino, R M; Rivera, M et al. (1992) Human studies with the chelating agents, DMPS and DMSA. J Toxicol Clin Toxicol 30:505-28
Akins, J M; Schroeder, J A; Brower, D L et al. (1992) Evaluation of Drosophila melanogaster as an alternative animal for studying the neurotoxicity of heavy metals. Biometals 5:111-20

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