succimer and methylmercuric-chloride

Chelation therapy for the treatment of acute, high dose exposure to heavy metals is accepted medical practice. However, a much wider use of metal chelators is by alternative health practitioners for so called "chelation therapy". Given this widespread and largely unregulated use of metal chelators it is important to understand the actions of these compounds. We tested the effects of four commonly used metal chelators, calcium disodium ethylenediaminetetraacetate (CaNa2EDTA), D-penicillamine (DPA), 2,3 dimercaptopropane-1-sulfonate (DMPS), and dimercaptosuccinic acid (DMSA) for their effects on heavy metal neurotoxicity in primary cortical cultures. We studied the toxicity of three forms of mercury, inorganic mercury (HgCl2), methyl mercury (MeHg), and ethyl mercury (thimerosal), as well as lead (PbCl2) and iron (Fe-citrate). DPA had the worst profile of effects, providing no protection while potentiating HgCl2, thimerosal, and Fe-citrate toxicity. DMPS and DMSA both attenuated HgCl2 toxicity and potentiated thimerosal and Fe toxicity, while DMPS also potentiated PbCl2 toxicity. CaNa2EDTA attenuated HgCl2 toxicity, but caused a severe potentiation of Fe-citrate toxicity. The ability of these chelators to attenuate the toxicity of various metals is quite restricted, and potentiation of toxicity is a serious concern. Specifically, protection is provided only against inorganic mercury, while it is lacking against the common form of mercury found in food, MeHg, and the form found in vaccines, thimerosal. The potentiation of Fe-citrate toxicity is of concern because of iron's role in oxidative stress in the body. Potentiation of iron toxicity could have serious health consequences when using chelation therapy.

Topics: Animals; Brain Chemistry; Cell Death; Cells, Cultured; Cerebral Cortex; Chelating Agents; Drug Synergism; Edetic Acid; Female; Iron; Lead; Mercuric Chloride; Methylmercury Compounds; Mice; Penicillamine; Pregnancy; Succimer; Thimerosal; Unithiol

Methylmercury (CH3Hg+) is a serious environmental toxicant. Exposure to this metal during pregnancy can cause serious neurological and developmental defects in a developing fetus. Surprisingly, little is known about the mechanisms by which mercuric ions are transported across the placenta. Although it has been shown that 2,3-dimercaptopropane-1-sulfonate (DMPS) and 2,3-dimercaptosuccinic acid (DMSA) are capable of extracting mercuric ions from various organs and cells, there is no evidence that they are able to extract mercury from placental or fetal tissues following maternal exposure to CH3Hg+. Therefore, the purpose of the current study was to evaluate the ability of DMPS and DMSA to extract mercuric ions from placental and fetal tissues following maternal exposure to CH3Hg+. Pregnant Wistar rats were exposed to CH3HgCl, containing [203Hg], on day 11 or day 17 of pregnancy and treated 24 h later with saline, DMPS or DMSA. Maternal organs, fetuses, and placentas were harvested 48 h after exposure to CH3HgCl. The disposition of mercuric ions in maternal organs and tissues was similar to that reported previously by our laboratory. The disposition of mercuric ions in placentas and fetuses appeared to be dependent upon the gestational age of the fetus. The fetal and placental burden of mercury increased as fetal age increased and was reduced by DMPS and DMSA, with DMPS being more effective. The disposition of mercury was examined in liver, total renal mass, and brain of fetuses harvested on gestational day 19. On a per gram tissue basis, the greatest amount of mercury was detected in the total renal mass of the fetus, followed by brain and liver. DMPS and DMSA reduced the burden of mercury in liver and brain while only DMPS was effective in the total renal mass. The results of the current study are the first to show that DMPS and DMSA are capable of extracting mercuric ions, not only from maternal tissues, but also from placental and fetal tissues following maternal exposure to CH3Hg+.

Topics: Animals; Brain; Brain Chemistry; Chelating Agents; Female; Fetal Weight; Fetus; Gestational Age; Hazardous Substances; Injections, Intravenous; Kidney; Liver; Maternal Exposure; Maternal-Fetal Exchange; Mercury; Methylmercury Compounds; Organ Size; Placenta; Pregnancy; Random Allocation; Rats; Rats, Wistar; Succimer; Tissue Distribution; Unithiol

The effect of methylmercury chloride (MMC) toxicity and its antagonism by chelating agents (N-acetyl-DL-homocysteine thiolactone and 2,3-dimercaptosuccinic acid) on succinic dehydrogenase (SDH) activity of fore-, mid-, and hindbrain and trigeminal ganglia of rats is reported in this study. A dose of 10 mg MMC/kg body weight was injected subcutaneously for 2, 7, and 15 days. The chelating agents were also injected subcutaneously in two separate groups of MMC-treated animals except in group 3. In the latter case MMC was injected in two groups of rats for 7 days, and thereafter antagonists were administered daily (40 mg/kg) for 1 week. The result shows inhibition of the enzyme with MMC in all groups and its restoration by N-acetyl-DL-homocysteine thiolactone; 2,3-dimercaptosuccinic acid, however, further reduced the enzyme level. The significance of inhibition of the enzyme in relation to tissue respiration and ATP production is discussed and the capacities of antagonists in the restoration of the SDH level are also analyzed.

Topics: Animals; Brain; Chelating Agents; Enzyme Reactivators; Ganglia, Spinal; Male; Methylmercury Compounds; Rats; Succimer; Succinate Dehydrogenase; Thiophenes

The effects of thiol compounds on methylmercury chloride (MMC)-inhibited choline acetyltransferase (ChAT) activity and MMC-inhibited high affinity choline uptake of rat brain tissue were studied in vitro. D-penicillamine (D-Pc) and dimercaptosuccinic acid (DMS) reversed the MMC-inhibited ChAT activity dose-dependently. Equilibrium dialysis of MMC-inhibited ChAT against the buffer containing 10(-3) M D-Pc reversed the ChAT activity almost completely. The reversal effect of D-Pc (monothiol compound) on MMC-inhibited ChAT was significantly more potent than that of DMS (dithiol compound). D-Pc and DMS almost equally reversed the MMC-inhibited high affinity choline uptake by synaptosomes in a dose dependent fashion. Washing with a solution containing D-Pc or DMS equally reversed the MMC-inhibited high affinity choline uptake in a dose-dependent fashion. Neither D-Pc nor DMS could reverse the hemicholinium-3-inhibited high affinity choline uptake.

Topics: Absorption; Animals; Brain; Chelating Agents; Choline; Choline O-Acetyltransferase; Dialysis; Male; Methylmercury Compounds; Penicillamine; Rats; Rats, Inbred Strains; Succimer; Sulfhydryl Compounds

Male albino rats were injected i.p. with [203Hg]methylmercuric chloride (MMC) and later at different time intervals they received N-acetylpenicillamine, 2,3-dimercaptopropane-1-sulfonate or dimercaptosuccinic acid (DMSA). The animals were sacrificed 24 h after the last chelant treatment and the content of 203Hg was determined in 10 organs. In liver and kidneys, [203Hg]MMC and 203Hg++ were measured separately. DMSA was most effective in removing the mercurial from all organs, except the kidneys, where 2,3-dimercaptopropane-1-sulfonate was better. N-acetylpenicillamine showed only marginal effectiveness. Separate determinations of [203Hg]MMC and 203Hg++ in liver and kidneys showed that DMSA removed more of the organic and 2,3-dimercaptopropane-1-sulfonate more of the inorganic Hg. DMSA injected i.p. or given p.o. removed almost equal amounts of MMC, indicating virtually 100% absorption of the chelating agent from the gastrointestinal tract.

Topics: Animals; Biotransformation; Chelating Agents; Male; Methylmercury Compounds; Penicillamine; Rats; Succimer; Tissue Distribution; Unithiol