DMSA and DMPS-Water Soluble Antidotes for Heavy Metal Poisoning

Abstract

This article reviews the pharmacological properties and the uses of two important antidotes for heavy metal poisoning. Meso-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-l-propanesulfonic acid, Na salt (DMPS) are relatively new antidotes-new, that is, to the western world. Although DMSA was introduced originally by Friedheim et al (1) to increase uptake of antimony during schistosomiasis therapy, Liang et al (77) at Shanghai in 1957 were the first to report its effectiveness as an antidote for heavy metallpoisoning. The synthesis and some of the metal binding properties of DMPS were reported in 1956 by Petrunkin from Kiev (3). Shortly thereafter, DMPS became an official drug in the Soviet Union, where it is known as Unithiol (4). Between 1956 and 1975, DMSA and DMPS were studied extensively, at both the basic science and clinical levels, in the People's Republic of China, the Soviet Union, and Japan. Some of these investigations have been cited and can be found in an earlier review (5). In the USA and western Europe, however, these two compounds received very little attention until recently. A paper by Friedheim & Corvi (6) in 1975, dealing with DMSA for the treatment of mercury poisoning, and the recent production and availability of DMPS from Heyl & Co., Berlin, stimulated investigators to "rediscover" and study these two metal-binding agents. DMSA and DMPS are water soluble chemical analogs of dimercaprol (British Anti-Lewisite, BAL). In contrast to BAL, they have less toxicity, greater water solubility, and limited lipid solubility, and are effective when given orally. * Important notes are marked. 193 If levels of heavy metals such as arsenic, lead, mercury, and cadmium continue to increase in the environment (7), the need will increase also for more effective, therapeutically useful antidotes to treat poisoning by these metals. This need might be met, in the future, by either DMSA, DMPS, or both. They are replacing BAL in the experimental laboratory and in some clinical situations, as discussed below. All of the papers published on DMSA and DMPS cannot be cited in this review. Space limitations have been imposed on an already lengthy bibliography. Many Chinese, Soviet, and Japanese papers have been translated, reviewed, and included. An emphasis has been placed, though, on important articles published since 1975. GENERAL AND CHEMICAL PROPERTIES DMSA and the sodium salt of DMPS are available as white crystalline powders. BAL is an oily liquid. Chemical formulas can be found in an earlier review (5). DMPS has been prepared as the racemic mixture (3), dextro-rotatory form and levo-rotatory form (W. Parr, personal communication). Studies using the D-or L-form, however are rare. In the literature and in this article, the abbreviation DMPS, unless otherwise stated, denotes the racemic mixture of the sodium salt of 2,3-dimercapto-l-propanesulfonic acid. Since DMSA has two asymmetric carbon atoms, the compound exists as the meso form and the DL form. Meso-DMSA is easier to prepare, more readily available, and h...

Thiol compounds inhibit mercury-induced immunological and immunopathological alterations in susceptible mice

“…Several studies on the treatment of mercury intoxication have shown that the route of administration of meso-DMSA and/or DMPS has little or no influence [11,12]. In concordance, we found that identical doses of DMPS, when given by either the i.p or s.c. route, had similar preventive effects on mercury-induced autoimmunity.…”

“…First, thiol compounds interfere with the binding of mercury to free sulfhydryl groups of proteins on cells of the immune system. Therefore, it is likely that free thiol groups present on thiol compounds bind to mercury directly, thus preventing the binding of mercury to lymphocyte surface proteins containing sulfhydryl groups [11][12][13]. Second, as reducing reagents, thiol compounds have the potential to protect sulfhydryl groups on cell surface proteins from oxidation [28,29], and thus it is possible that they are able to release bound mercury from cell surface proteins.…”

“…The efficacy of meso-DMSA and DMPS in the treatment of mercury intoxication or in mobilizing mercury compound has been extensively studied in humans as well as in experimental animals [11][12][13]. In rats the influence of meso-DMSA and DMPS on the distribution and excretion of mercuric chloride as well as methylmercury has been compared [30,31].…”

“…To analyse further whether the other thiol compounds also have similar effects, we tested the four thiol compounds with a chemical structure close to 2-ME, i.e. DTT, L-cysteine [6], meso-DMSA and DMPS [11][12][13] at various concentrations from 0 . 01 mM to 100 mM.…”

“…Our in vitro findings that thiol compounds inhibited mercuryinduced cell aggregation and cell proliferation led us to test whether any of these agents could also prevent or dampen in vivo mercury-induced immunological alterations. Since meso-DMSA and DMPS have been used successfully to treat heavy metal poisoning, including mercury [11,12], and since their chemical, pharmacological and toxicological properties have been extensively studied [11,12], we selected a concentration of 30 mg/ kg body weight of these two antidote drugs for our in vivo studies. This concentration was found to be effective and not toxic ( [12], H. V. Aposhian, personal communication, and our own observation).…”