Effect Of BAL Research Articles

2,3‐Dimercapto‐1‐propanol does Not Alter the Porphobilinogen Synthase Inhibition but Decreases the Mercury Content in Liver and Kidney of Suckling Rats Exposed to HgCl2

Heavy metals have received great attention as environmental pollutants mainly because once introduced in the biological cycle they are incorporated in the food chain. Especially the mercury toxicity due to a diversity of effects caused by different chemical species should be emphasized. Heavy metal intoxication has been treated with chelating agents such as 2,3-dimercapto-1-propanol (BAL). However, the efficacy of this treatment is questionable due to the lack of specific effect on the toxic metal. The present study examined the effects of HgCl2 exposure (five doses of 5.0 mg/kg between ages 8 to 12 days) on physiological parameters, on porphobilinogen synthase activity, and on mercury content in liver, kidneys and brain from suckling rats. The effect of BAL (one dose of 12.5-75 mg/kg) applied 24 hr after mercury intoxication on these parameters was also investigated. The results demonstrate that HgCl2 intoxication induced a decrease of corporal weight gain as well as brain weight and an increase in renal weight. The inhibition of porphobilinogen synthase from liver and kidney, is still significant and was not modified by subsequent BAL treatment. However, BAL altered two effects induced by mercury: increase in death percentage and decrease in mercury contents in liver and kidney. The increase of mortality induced by mercury was not promoted by metal redistribution to brain nor by the increase of porphobilinogen synthase inhibition induced by metal. More investigations are necessary to determine if the different effects of BAL on intoxication by metals are possibly related to other tissues and/or if the probable metal-chelating complex formed is more toxic than the metal itself.

Effect of dithiol chelating agents on [3H]MK-801 and [3H]glutamate binding to synaptic plasma membranes.

2,3-Dimercaptopropanol (BAL- British Anti-Lewesite) is a dithiol chelating agent used for the treatment of heavy metal poisoning, however, BAL can produce neurotoxic effects in a variety of situations. Based on the low therapeutic efficiency of BAL other dithiols were developed and DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercaptopropane-1-sulfonic acid) are becoming used for treatments of humans exposed to heavy metals. In the present investigation the effect of dithiols in the glutamatergic system was examined. The results showed that BAL inhibited [3H]MK-801 and [3H]glutamate binding in a concentration-dependent manner. At 100 microM BAL and DMSA caused a significantly inhibition of [3H]MK-801 binding to brain membranes (p < 0.05 by Duncan's multiple range test). BAL at 100 microM caused an inhibition of 40% on [3H]glutamate binding. DMPS and DMSA had no significant effect on [3H]glutamate binding. Dithiotreitol (DTT), abolished the inhibitory effect of BAL on [3H]MK-801 binding. The protection exerted by DTT suggests that BAL inhibit [3H]MK-801 binding by interacting with cysteinyl residues that are important for redox modulation of receptor responses. ZnCl2 inhibited [3H]glutamate and [3H]MK-801 binding to brain synaptic membrane; nevertheless, the inhibitory effect was slight more accentuated for [3H]MK-801 than [3H]glutamate binding (p < 0.05). The inhibition caused by 10 microM ZnCl2 on [3H]MK-801 binding was attenuated by BAL. The findings present in this study may provide the evidence that BAL affect the glutamatergic system and these effects can contributed to explain, at least in part, why BAL, in contrast to DMPS and DMSA is neurotoxic.

Reducing reagent-induced activation of adenylate cyclase in the cellular slime mold, Dictyostelium discoideum.

Binding of an intrinsic agonist (cAMP) to specific receptors on the cell surface induces transmembrane signals for activation and desensitization (adaptation and down regulation) of adenylate cyclase in the cellular slime mold, Dictyostelium discoideum. It is generally believed that dithiothreitol (DTT) induces the activation through interaction between the receptor and gradually accumulated cAMP, since DTT is known to inhibit cAMP-phosphodiesterase which degrades cAMP. In the present paper, we investigated the mechanism of activation of adenylate cyclase by the thiol-reducing agents, DTT and 2,3-dimercapto-1-propanol (BAL). We found that BAL activated adenylate cyclase transiently even under conditions where the intrinsic agonist supersaturated the cAMP-receptors and competitively inhibited phosphodiesterase. This result is inconsistent with the generally accepted notion. We conclude that BAL has an independent effect from those of the intrinsic agonist (cAMP) and phosphodiesterase in activation of adenylate cyclase. Since BAL could induce activation just after the activation induced by a supersaturating concentration of the intrinsic agonist had ceased, the independent effect of BAL is not a simple enhancement of the cAMP-induced activation. Our result also suggests that the cAMP-induced adaptation (but not down regulation) suppresses the BAL-induced activation while BAL itself does not induce adaptation to cAMP or BAL. We propose that the thiol-reducing reagent induces or modifies the transmembrane activation signal for adenylate cyclase.

Effect of oral treatment with Bal, DMPS or DMSA arsenic in organs of mice injected with arsenic trioxide.

The dithiols DL-2,3-dimercaptopropanol (British Anti-Lewisite, BAL; Peters et al 1945), DL-2,3-dimercaptopropanesulfonate (DMPS; Petrunkin 1956) and meso-2,3-dimercaptosuccinic acid (DMSA; Liang et al 1957) are effective arsenic antidotes. The possibility of oral application to reduce the As2O3 toxicity is proved for DMPS and DMSA, but not for BAL. Why BAL should not be given orally has not been discussed (Aposhian 1983; lit. in press). On the other hand, in one paper so far (Kreppel et al 1989) oral treatment with BAL has been shown to be effective in reducing lethality in acute As2O3 poisoning. Hence, the effectiveness of BAL in hydrophilic and in lipophilic solvent, DMPS, and DMSA in reducing the arsenic content of tissues after oral administration was investigated.

The activating mechanism of human plasminogen through streptokinase. Inhibition experiments with BAL.

In view of an alleged direct activator action of streptokinase (SK) on human plasminogen the inhibitory effect of BAL on the activation of human plasminogen through SK was compared with that through u

Hg&lt;sup&gt;203&lt;/sup&gt;(NO&lt;sub&gt;3&lt;/sub&gt;)&lt;sub&gt;2&lt;/sub&gt;を用いた水銀中毒に関する実験的研究

With the purpose to find out the effect of BAL (2.3 Dimercaptopropanol) in mercury poisoning, a group of guinea pigs were divided into two gruops of A group (control) and B group (BAL injection). To A group 1, 200, 000 c. p. m./kg of radio isotope Hg203(NO3)2 (0.026 mg/kg of mercury) was injected into the dorsal muscle, and to B group the same dose of Hg203(NO3)2 was given in the same way and immediately 20 mg/kg of BAL was injected and the same dose for the six consecutive days thereafter. Then, for the period of one week following the injection of Hg203(NO3)2, the excretion of mercury in the urine and stool as well as the distribution of mercury combined with protein in the intracellular granules of kidney after one week of Hg203(NO3)2 injection were observed in order to see the antidotal effect of BAL, and obtained the following results.1. With the control group, the observations conducted with the lapse of time after Hg203(NO3)2 injection have revealed that the excretion of mercury in the urine is greatest on the second day, the excreted amount being about 21 per cent of the total mercury excreted in the urine in the one week period of observation. This excretion decreases relatively rapidly thereafter, but a transient rise in the quantity of excreted mercury can be observed on the fourth day.As for the excretion of mercury in stool, it tends to increase from the first day to the fifth day of the observation showing the greatest amount of the excretion on the fifth day and after that it decreases relatively rapidly.2. In the group injection with BAL, the excretion of mercury in the urine is markedly great on the second day, this amount being as much as about 31 per cent of the total mercury excreted during the one-week period of observation, and it decreases quite rapidly thereafter.On the other hand, the amount of mercury excreted in the stool increases gradually from the first day to the third day of observation, showing the greatest amount of the excretion on the third day which is two days earlier than that in the control, and it decreases relatively slowly thereafter.3. In the control group, the sum of the total amounts of mercury excreted in the urine and stool for the period of one week is about 49.8 per cent of the mercury injected, and of this about 35.9 per cent is excreted in the urine and that in the stool about 13.9 per cent, proving that the amouut excreted in the urine to be as much as about 2.6 times that in the stool.4. In the group injected with BAL, the sum of the total amounts of mercury excreted in the urine and stool for the one-week period is about 82.7 per cent of the mercury injected, and of this about 69.5 per cent is excreted in the urine and about 13.2 per cent in the stool, proving that the amount of mercury excreted in the urine is about 5.3 times that in the stool.From the findings described in sections 3 and 4, in the group B given BAL, the amount of mercury excreted in the urine during the one-week period is about 69.5 per cent of the injected mercury, whereas that in the stool is about 35.9 per cent in the control A group, proving that the BAL administration has a marked effect on the excretion of mercury in the urine. On the other hand, the amount of mercury excreted in the stool is 13.2 per cent in the B group given BAL as against about 13.9 per cent in the A group, control. This means that there is hardly any effect of BAL on the excretion of mercury in the stool.5. In the observation of the B group given BAL, the amount of the mercury combined with protein in kidney tissue has been found to decrease markedly after the BAL injection, and the amount of mercury cmbined with protein per 1.0 mg.

Value and Complications of Gold Therapy in Rheumatoid Arthritis

SummaryThe mechanism by which gold acts in rheumatoid arthritis is not properly understood. It is only known that the gold compounds block the SH groups of glutathione, cysteine and perhaps other sulfhydryl compounds in the body and partly inhibit normal oxireduction processes in the cells.Thus also the mechanism by which the toxic reactions of gold therapy are produced is obscure. It must be some form of idiosyncrasy. The beneficial effect of BAL in such cases might be explained by its ability to break down the gold protein bond through competing effectively with the sulfhydryl groups of various tissue proteins for the gold. If BAL is given early and in adequate doses, all the reactions disappear.To use adrenocorticoids as the only therapeutic agent in gold reactions involves the risk of controlling the symptoms without due regard to the fact that the causing agent is still remaining. In many cases chronic pathologic skin changes persist. Auridosis will be one of its sequels.

Peripheral neuropathy caused by arsenical intoxication; a study of 41 cases with observations on the effects of BAL (2, 3, dimercapto-propanol).

EARLY in the present century lesions of the peripheral nerves caused by arsenical intoxication were a frequent occurrence. In most cases the neuropathy could be attributed to contact with the many household articles such as dyes, wallpaper and insecticides that contained large quantities of arsenic. In recent years, exposure to arsenic has been greatly reduced, and arsenical intoxication is no longer considered a common cause of peripheral neuropathy. Dusts and sprays containing arsenic, however, continue to be extensively employed as pesticides on farms in North Carolina, and their accidental ingestion or inhalation has produced numerous cases of poisoning. Our experience . . .

Toxicity of dextran in rats.

THE anaphylactoid reaction caused by dextran in rats has recently been studied by several investigators1–3. We have found that after intradermal injections of dextran dissolved in physiological saline (in rats), Menkin's intravenous dye test4 shows a seepage of dye into the wheals when the concentration of commercial dextran (Macrodex, Pharmacia Inc.) is at least 10 µgm/ml. Moreover, it has been found that dextran preparations with highly branched molecular chains are more toxic than those with relatively unbranched chains. Dextran fractions of an average molecular weight of 10,000 cause a positive dye test only in concentrations of about 10 mgm./ml. Sulphuric acid esters of dextran5 do not cause increased capillary permeability. We have confirmed the previously reported increase in hæmatocrit values after intravenous injection of dextran3, and found that it is more or less completely prevented by antihistaminics, local anæsthetics and pretreatment with cortisone in high doses. The most potent inhibitor, however, is alloxan intravenously in a subdiabetogenic dose. 2,3-Dimercaptopropanol injected 30 min. before dextran has an inhibitory effect only in some experimental series. The factors causing these variations in the ‘antiphlogistic’ effect of BAL are under study.

Effect of BAL on survival of rats after lethal doses of polonium.

Summary(1) Control rats injected with a lethal dose of polonium (36 μc/kg) had a median survival time of 22 days, whereas the BAL-treated group had a median survival time of 89 days. (2) Blood studies of control rats showed the typical picture of hemopoietic failure in contrast with well sustained cell and platelet levels found for the BAL-treated group. The difference is believed to be due to a reduced radiation exposure of the spleen and marrow caused by the action of BAL in accelerating excretion and in diverting polonium from the hemopoietic organs into muscle.

The effects of BAL on the metabolism of lead and on the symptomatology in lead intoxication.

The effects of injection of BAL on the metabolism of lead has been studied by Eagle (1948) and by Ginsburg and Weatherall (1948) in animals poisoned with lead acetate, and by Ryder, Cholak, and Kehoe (1947) in human cases of acute lead poisoning. The action of BAL has been shown to be the same both in experimental animals and in man ; in animals it had no demonstrably protective action, and on occasion appeared to accelerate the toxic effects of lead acetate in rabbits ; similarly in man, three days' treatment with 1-7 g. of BAL was without beneficial effect. Characteristic effects were observed on the metabolism of lead, inasmuch as there followed a rapid drop in the lead concentration in the red blood cells, and an immediate rise in urinary lead concentration, to a degree far greater than that observed from any other kind of treatment. The plasma and faecal lead concentration were un changed by BAL treatment. Eagle (1948) advised caution in the use of BAL, although he did not see evidence in man of toxic effects in cases of lead poisoning. He recom mended four-hourly injections of 2-5 mg. per kg. body weight repeated four times a day and con tinued for two to four days, diminishing thereafter gradually to about two injections a day. Ginsburg and Weatherall (1948) used the Th. ? isotope of lead to study lead acetate distribution in tissues. Administration of lead acetate was followed by 50 mg. per kg. BAL up to 23 hours later. This resulted in increased urinary excretion of lead and a shift in the tissue distribution from the liver, the spleen, the red cells, and the bone marrow to the skeletal and cardiac muscle. Our studies on BAL treatment in human cases of lead intoxication were started two years before read

The effect of BAL on distribution and metabolism of P32 and Sr90.

SummaryThe effectiveness of 2,3-dimer-captopropanol (British anti-lewisite) in increasing the elimination of injected P32 and Sr90 in mice was investigated. It is concluded that BAL is essentially without effect although, in the case of P32, the rate of uptake in bone appears to be reduced during the first hour. No such differences could be demonstrated after 24 hours.

Administration of BAL in selenium poisoning.

Selenium causes “alkali disease” or “blind staggers” in livestock in the Dakotas, Kansas, Montana, Wyoming, and other Western States where the soil and vegetation are high in selenium content. Therefore the toxic properties of selenium and its compounds are of great importance in these areas. As far as we know, there is no reliable agent which is of value in preventing or curing the symptoms of selenium poisoning, though protective action of arsenic has been demonstrated by Moxon et al. Peters, Stocken, and Thompson described the effectiveness of BAL in counteracting the effects of arsenical poisoning. The protective action of this compound in arsenical poisoning was believed to be due to the release of SH groups by BAL which could compete with the tissue SH groups for the arsenic, and act as a detoxifying agent. The nature of the reaction between arsenic and BAL made it seem probable that BAL would react similarly with other metals, and Gilman, Allen, and Philips have reported its effectiveness as an antidote for bichloride of mercury and cadmium poisoning, and Braun, Lusky, and Calvery showed similar results against poisoning by antimony, bismuth, chromium and nickel. However, they demonstrated that lead and selenium were made more toxic by BAL. Our experiments performed using BAL as an antagonist against selenium poisoning confirmed the results already described However, we have found no explanation in the literature of the apparent synergism between BAL and selenium, hence our work has been directed along this line. Experimental. Healthy white rats 6 to 8 weeks old, 120 and 150 g of weight were used. Selenium was administered by intraperitoneal injections in the form of a freshly prepared aqueous solution of sodium selenite (SS).

Effect of BAL on Cobalt-induced Polycythemia in Rats

ConclusionsBAL in a dose of 0.2 mM/kg given 3 times weekly fails to prevent, cure, or materially alter cobalt-induced polycythemia in rats. The general toxicity of BAL appears minimal when given in this dosage over a 3½-month period.

Effect of BAL on Trichomonacidal Activity of Some Organic Arsenicals

1. The condensation with BAL enhances significantly the trichomonacidal effect of Mapharsen.