Inactivation of enteroviruses by 2,3-dimercaptopropanol (BAL).
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Dimercaprol↗
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Biological chelation: 2,3-dimercapto-propanesulfonic acid and meso-dimercaptosuccinic acid.
Water soluble analogs of British Anti-Lewisite that are active orally and less toxic than BAL are now available. These agents are 2,3-dimercapto-1-propanesulfonic acid and meso-dimercaptosuccinic acid. Evidence for their effectiveness in preventing the lethal effects of sodium arsenite in mice and lewisite in rabbits is presented. These analogs can be expected to replace BAL in the treatment of heavy metal poisoning.
Animals↗
Elevated antigalactosyl antibody titers reflect renal injury after gold or D-penicillamine in rheumatoid arthritis.
Titers of circulating antigalactosyl antibodies (a-Gal Ab) were assessed by passive hemagglutination using rabbit red blood cells in 40 normal subjects, in 14 patients with immunodeficient states, in 47 patients with active rheumatoid arthritis (RA), and in 15 patients with an Henoch-Schönlein disease (HS). Titers of controls ranged from 1:16 to 1:64. All immunodeficient patients exhibited very low titers (1:1). On the contrary, the existence of an enhanced humoral immune response status, as observed in RA, was not reflected by a parallel increase of a-Gal Ab titers. However, in this disease, a strong relationship existed between titers exceeding control values (greater than 1:64) and the prior occurrence of renal injury under gold or D-penicillamine therapy. Lastly, the discovery of elevated titers (greater than 1:64) in HS only when renal involvement occurred further suggests that such antibodies reflect a renal injury.
Acquired Immunodeficiency Syndrome↗
Effects of Mel B arsobal and alpha-difluoromethylornithine on the awakening electroencephalogram of humans with gambiense trypanosomiasis disease: preliminary report.
Five males and three females, at the encephalic stage of sleeping sickness, were submitted to trypanocide therapies. Three of the patients were treated with the Mel B Arsobal drug, the five others with difluoromethylornithine, using different protocols. Awakening electroencephalographic data were obtained prior to treatment and, at regular intervals, during and after treatment. Prior to treatment the awakening tracings showed important abnormalities (slow delta waves were superimposed on theta background rhythms). During treatment (except in one patient treated with Arsobal) recordings returned gradually to fast rhythms and several days after therapy, tracings returned to the normal awakening patterns. The use of the awakening electroencephalogram as a tool to test effects of curative drugs in the sleeping sickness syndrome is discussed.
Adolescent↗
Amelioration by BAL (2,3-dimercapto-1-propanol) and DMPS (sodium 2,3-dimercapto-1-propanesulfonic acid) of arsenite developmental toxicity in mice.
Inorganic arsenic is embryotoxic and teratogenic in chicks, golden hamsters, mice, and rats. Certain dithiol chelators have been reported to protect against arsenite-induced lethality and to decrease arsenic body burden. The present study evaluated the influence of BAL (2,3-dimercapto-1-propanol) and DMPS (sodium 2,3-dimercapto-1-propanesulfonic acid), a water-soluble analogue of BAL, on arsenic-induced embryotoxic and teratogenic effects in the mouse. A series of four BAL or DMPS injections was administered sc to pregnant mice immediately after a single ip injection of 12 mg/kg of sodium arsenite given on Day 9 of gestation and at 24, 48, and 72 hr thereafter. Controls received sc corn oil with or without arsenite. Amelioration by BAL and DMPS of arsenite developmental toxicity was assessed at 15, 30, and 60 mg/kg/day, and 75, 150, and 300 mg/kg/day, respectively. BAL given following arsenite was not able to ameliorate the developmentally toxic effects of arsenite seen in mice, whereas treatment with DMPS at 150 and 300 mg/kg showed significant protective effects against arsenite embryotoxicity and teratogenicity. DMPS administration at 300 mg/kg also protected the dams against arsenite-induced maternal toxicity.
Animals↗
Reactive sulfhydryl groups in Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase.
Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase (ATP:oxaloacetate carboxy-lyase (transphosphorylating), EC 4.1.1.49) is inactivated by several thiol- and vicinal dithiol-specific reagents. Titration experiments of the enzyme with 5,5'-dithiobis(2-nitrobenzoate) (DTNB) show the presence of reactive monothiol and vicinal dithiol groups, whose modifications lead to enzyme inactivation. The enzyme is also inactivated by N-(1-pyrenyl)iodoacetamide (PyrIAM), with a binding stoichiometry of approx. 2 mol per mol of enzyme subunit. A high level of pyrene excimer fluorescence is detected on the labeled enzyme, thus implying the reaction of the reagent with two spatially close sulfhydryl groups in the protein. The carboxykinase is not completely inactivated by different vicinal dithiol-specific reagents, thus implying a catalytically non-essential character for these groups. From substrate protection experiments of the enzyme inactivation by DTNB, PyrIAM and vicinal dithiol-specific reagents, it is concluded that the loss of enzyme activity is caused by the modification of both thiol and vicinal dithiol groups in the substrate binding region.
Arsenic↗
DMSA, DMPS, and DMPA--as arsenic antidotes.
meso-Dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propanesulfonic acid, Na salt (DMPS), and N-(2,3- dimercaptopropyl )- phthalamidic acid (DMPA) are water soluble analogs of 2,3-dimercapto-1-propanol (BAL). The relative effectiveness or therapeutic index of these dimercapto compounds in protecting mice from the lethal effects of an LD99 of sodium arsenite is DMSA greater than DMPS greater than DMPA greater than BAL in the magnitude of 42:14:4:1, respectively. DMPS, DMPA, or DMSA will mobilize tissue arsenic. BAL, however, increases the arsenic content of the brain of rabbits injected with sodium arsenite. These results raise the question as to the appropriateness of BAL as the treatment for systemic arsenic poisoning. Either DMSA or DMPS, when given sc or po, will protect rabbits against the lethal systemic effects of subcutaneously administered Lewisite . DMPS and DMSA have promise as prophylactics for the prevention of the vesicant action of Lewisite . The sodium arsenite inhibition of the pyruvate dehydrogenase (PDH) complex can be prevented and reversed in vitro or in vivo by DMPS, DMSA, DMPA, or BAL. Of them all, DMPS is most potent and BAL appears to be the least potent. The usefulness of all these dimercapto compounds would be enhanced by a careful study of their metabolism and biotransformation. These dimercapto compounds are in a great many respects orphan drugs. At this stage of their development, it is very difficult for the clinician to obtain funds to study them clinically even though they appear to be useful for treatment of poisoning by any one of the heavy metals.
Animals↗
Arsenic distribution in rabbits after Lewisite administration and treatment with British anti-Lewisite (BAL).
The standard treatment of Lewisite (dichloro(2-chlorovinyl)arsine) poisoning is by chelation with BAL (British anti-Lewisite, dimercaptopropanol). The present study investigated the effect of BAL treatment on the distribution of arsenic after Lewisite administration. Lewisite was administered subcutaneously at the LD10 and LD40 of the compound. Without BAL treatment arsenic was eliminated with a half-life in blood of between 55 and 75 hr and a blood clearance of 120 ml/hr/kg. Arsenic had a large volume of distribution of several liters per kilogram, indicating extensive distribution in tissues. The highest tissue concentrations, more than seven times blood concentrations, were found in the liver, lung, and kidneys. These organs maintained an approximately constant concentration ratio with blood during the sampling period. Concentrations in tissues with a blood-to-tissue barrier, such as the brain and the spinal cord, rose between 4 and 96 hr while blood concentrations declined more than fourfold over the same time period. BAL treatment by four equal, maximally tolerated doses over 12 hr substantially reduced arsenic concentrations in blood and tissues. For example, at 24 hr the concentrations in brain and liver (target organs for arsenic toxicity) were reduced by 65 to 89% over the range of Lewisite doses administered. The total exposure of brain and spinal cord was reduced by more than two-thirds by BAL treatment. Further, the blood clearance of arsenic was increased. BAL treatment enhanced the elimination of arsenic in two ways: by decreasing the tissue-to-blood partitioning which mobilizes arsenic into the blood stream, and by increasing the clearance of arsenic.
Adipose Tissue↗
The excretion of trace elements in rat urine after treatment with 2,3-dimercaptopropane sodium sulfonate.
Administration of various doses of the chelating agent 2,3-dimercaptopropane sodium sulfonate (Dimaval, DMPS) leads to a greatly enhanced excretion of Zn and Cu. The excretion of Co, Mn, Ni and Fe remains unchanged. The relevance of these findings to the toxicity of DMPS is discussed.
Animals↗
The effect of 2,3-dimercaptorpropane-1-sulfonate and dimercaptosuccinic acid on the distribution and excretion of mercuric chloride in rats.
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Animals↗
tri-n-Butyltin: a membrane toxicant.
Increased use of the biocidal compound tri-n-butyltin (TBT) in antifouling paints has prompted research aimed at determining the mechanism for TBT toxicity. Past investigations indicate that the primary cellular target for TBT is the cell membrane. Erythrocyte suspensions treated with TBT concentrations 2 greater than or equal to 5 microM undergo hemolysis described by a sigmoidal kinetic pattern. Transformation of cell shape from discocyte to echinocyte occurs at TBT concentrations greater than or equal to 0.1 microM, indicating that the compound enters the outer membrane bilayer. TBT at concentrations greater than or equal to 10 microM forms electron-dense aggregates that are intercalated within plasma membranes as viewed in ultrathin sections by transmission electron microscopy. Qualitative X-ray microanalysis of these aggregates confirms the presence of tin. The size of these structures can be modified by either 10 mM cyanide or 2,3-dimercaptopropanol (British Anti-Lewisite, BAL). Adding 10 mM cyanide to hemolytic TBT concentrations resulted in a synergistic stimulation of hemolysis attributable to high cyanide anion concentrations in or near the cell membrane. The elevated cyanide anion levels are thought to contribute to membrane lysis. The lipophilic dimercapto compounds BAL, dithiothreitol, and 2,3-dimercaptosuccinate are effective inhibitors of TBT-induced lysis. Water-soluble 2,3-dimercapto-1-propane sulfonate, a BAL analog, was largely ineffective as an inhibitor. The detailed molecular mechanism for TBT-induced membrane lysis is not yet clear. Cellular ATP depletion could be induced by TBT as well as by delipidation of anionic phospholipids or even formation of tributylstannylperoxy radicals, resulting in lipid peroxidation.
Chemical Phenomena↗
Influence of 2,3-dimercaptopropane-1-sulfonate and dimercaptosuccinic acid on the mobilization of mercury from tissues of rats pretreated with mercuric chloride, phenylmercury acetate or mercury vapors.
The efficiency of the sodium salt of 2,3-dimercaptopropanesulfonic acid (DMPS) and meso-dimercaptosuccinic acid (DMSA) to mobilize mercury from tissues has been assessed in rats pretreated with different doses of HgCl2, phenylmercury acetate or exposed to different concentrations of mercury vapors. These pretreatments increase the mercury concentration in the kidney and to a lower extent in the liver. Only exposure to metallic mercury vapor leads to mercury accumulation in the brain. Both chelators mobilize mercury stored in the kidney and the amount of metal excreted in urine following a single administration of DMSA is a good indicator of the renal burden of mercury. The rate of removal is greater after DMPS administration than after DMSA but repeated administration of either agents eventually leads to the same total amount of mercury mobilized from the kidney. The loss of mercury from the liver can be slightly accelerated by repeated administration of the chelators. However, the chelators are inefficient in removing mercury from the brain.
Administration, Inhalation↗
Evaluation of the developmental toxicity of 2,3-dimercapto-1-propanesulfonate (DMPS) in mice. Effect on mineral metabolism.
The sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS), a potent chelating agent used in the treatment of inorganic and organic heavy metal intoxications was evaluated for developmental toxicity in pregnant Swiss mice. DMPS was administered by gavage at doses of 0, 75, 150 and 300 mg/kg per day on gestational days 6-15. Females were evaluated for body weight gain, food consumption, appearance and behavior, survival rates and reproduction data. Cesarean sections were performed on gestation day 18. There were no maternal toxic effects, and no treatment-related changes were recorded in the number of total implants, resorption, the number of live and dead fetuses, fetal body weight or fetal sex distribution data. Gross external, soft tissue and skeletal examination of the DMPS-treated fetuses did not show significant differences at any dose in comparison with the controls. Mineral analysis of maternal and fetal tissues revealed slight effects of DMPS on metabolism of calcium, magnesium, zinc, copper and iron. The results of this study in mice indicate that DMPS is not a developmental toxicant at levels up to 300 mg/kg per day.
Abnormalities, Drug-Induced↗
Further study of effects of chelating agents on excretion of inorganic mercury in rats.
The effects of three chelating agents, N-benzyl-D-glucamine dithiocarbamate (BGD), 2,3-dimercaptopropanol (BAL) and D-penicillamine (D-PEN), on the excretion of mercury in rats exposed to mercuric chloride (HgCl2), the chemical forms of mercury compounds excreted in the bile and urine and the intestinal reabsorption of mercury compounds in the bile were studied. Rats were injected intraperitoneally with 203HgCl2 (300 micrograms Hg and 74 kBq of 203Hg/kg) and 24 h later, they were injected intraperitoneally with a chelating agent (a quarter of an LD50). The injection of the chelating agents significantly enhanced the biliary and urinary excretions of mercury. The enhancing effect of BGD on the excretions of mercury was almost the same as that of BAL and much larger than that of D-PEN. The major chemical form of mercury in the bile and urine of rats injected with BGD after HgCl2 treatment was Hg-BGD compounds. The chemical form of mercury in the bile and urine of rats injected with BAL after HgCl2 treatment was mainly Hg-GSH compound. The mercury after HgCl2 and D-PEN treatment was excreted mainly via the urine in the form of Hg-D-PEN compound. The intestinal reabsorption of mercury from the bile of rats injected with BGD or D-PEN was only 0.18% or 0.38% of the dose, respectively. The intestinal reabsorption of mercury from the bile of rats injected with BAL was 27.38% of the dose. It was suggested that the Hg-GSH compound excreted in the bile after HgCl2 and BAL treatment is partly degraded to Hg-cysteine (Cys) by the intestinal membranous enzymes and that the ligand of Hg-Cys is replaced by BAL in the bile, resulting in the effective reabsorption of Hg-BAL compound from the intestine.
Animals↗
Nuclear Magnetic resonance quadrupole relaxation studies of chloride binding to the isolated hemoglobins from trout (Salmo irideus).
NMR studies of chloride binding to the main components of trout blood, Hb Trout I and Hb Trout IV, indicate that although the affinity of chloride is high for both hemoglobins, the characteristics of the binding process are markedly differnet. In Hb Trout IV chemical exchange at the chloride binding site(s) is fast and quadrupole effects determine the linewidth; chloride binding has a definite pH dependence, but there is no significant oxygen linkage. In contrast Hb Trout I represents a unique case of slow chemical exchange, which may depend on unusual stereoche mical characteristics of the chloride binding site; chloride binding is pH independent, but shows a significant oxygen linkage, which may be attributed to changes of the lifetime of chloride at the binding site. The chloride binding properties displayed by Hb Trout I and IV have been compared with those of normal and modified human hemoglobins and discussed in terms of the structural differences in the C- and N-terminal regions of the alpha- and beta-chains.
Animals↗
Relationships between the copper atoms of caeruloplasmin. II. An interaction between the copper binding sites.
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Carbamates↗
Distribution and excretion of 203Hg2+ in rats after unitiol, spironolactone and polythiol resin treatment.
Rats were given 203HgCl2 i.v. at a dose level of 120 microgram of Hg2+ per rat. The effect of unitiol (UNI; sodium 2, 3-dimercaptopropanosulphonate) and a combined UNI, spironolactone (SPL) and polythiol resin treatment on wholebody retention, organ distribution and excretion were studied for 48 h. In both treated groups significant increases in excretion and decreases in whole-body retention of 203Hg were observed. In the combination-treated group significantly lower values of 203Hg in plasma, kidney and brain were found.
Animals↗
Effects of chelating agents on biliary and urinary excretion and tissue distribution of cadmium in rats.
Sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC), which was newly synthesized, sodium N-methyl-D-glucamine dithiocarbamate (NMG-DTC), and 2,3-dimercapto-1-propanol (BAL) were evaluated for their efficacy in mobilization of cadmium from the body using rats which had received cadmium, 30 min and 24 h earlier. At both 30 min and 24 h after treatment with cadmium, these chelating agents significantly enhanced the biliary excretion of cadmium, but did not influence the urinary excretion of the metal. Such an enhancement effect of NBG-DTC on the biliary excretion of cadmium was much larger than that of NMG-DTC or BAL. These chelating agents were effective in mobilizing cadmium from the liver at 30 min after pretreatment with cadmium. NBG-DTC showed the largest effectiveness on the depression of cadmium content in the liver. However, the contents of cadmium in the liver and kidney of rats given cadmium, 24 h earlier, did not significantly change at 3 h after treatment with the chelating agents. These results show that the injection of NBG-DTC at both 30 min and 24 h after treatment with cadmium can much more effectively mobilize cadmium from the body mainly through the bile without redistribution of cadmium to tissues than injection of NMG-DTC and BAL.
Animals↗