Dimercaprol (BAL) and detoxication with sulfhydril compounds.
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The production of a mercury amalgam in home gold ore processing has become a popular and widely used method. Six patients involved in two episodes were treated following onset of symptoms from inhalation of mercury vapor. Penicillamine was shown to be an effective chelator of mercury when coupled with a mobilization test to assess body burden. The danger associated with mercury use in this technique needs to be better communicated to the public.
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Several thiol blocking agents inhibit basal guanylate cyclase activity of 100 000 X g hepatic supernatant fractions and the stimulation of enzyme activity by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), NaN3, NaNO2 and nitroprusside. The relative potency of the thiol blockers as inhibitors was CdCl2 greater than p-hydroxymercuribenzoate greater than N-ethylmaleimide greater than arsenite greater than iodoacetamide. Inhibition of basal and MNNG-responsive soluble guanylate cyclase activities by arsenite was markedly potentiated by an equimolar concentration of 2,3-dimercaprol, but not by mercaptoethanol. Inhibition of soluble guanylate cyclase by either arsenite or CdCl2 was completely reversed by excess 2,3-dimercaprol. Qualitatively similar effects were observed with DE-52 cellulose purified soluble hepatic guanylate cyclase, and suggested an involvement of closely juxtaposed thiol groups in the regulation of enzyme activity. For several reasons inhibition by thiol blockers appeared to be mediated through multiple mechanisms and/or sites of interaction: (1) Concentrations of the thiol inhibitors which had no effect on basal activity strikingly inhibited the responsiveness of the enzyme to a submaximal concentration of MNNG. (2) CdCl2 abolished the action of excess MnCl2 to stimulate purified guanylate cyclase, but was a relatively ineffective inhibitor when MnCl2 and GTP were present in equimolar concentrations. By contrast, arsenite-2,3-dimercaprol was uniformly effective in inhibiting guanylate cyclase activity in the presence or absence of excess MnCl2. (3) Arsenite-2,3-dimercaprol increased the Km for MnGTP (control, 0.13 +/- 0.02 mM; 0.2 mM arsenite-2,3-dimercaprol, 0.31 +/- 0.03 mM), whereas CdCl2 had no effect on this parameter. (4) Hepatic particulate guanylate cyclase activity was significantly inhibited by arsenite 2,3-dimercaprol but not by CdCl2. Thus, the data not only indicate that vicinal dithiol groups are required for expression of basal guanylate cyclase activity and enzyme responses to agonists, but strongly suggest the involvement of more than one interacting site containing free thiol residues.
A series of studies investigated the conditioned flavor aversions induced by administration of either lead or thallium in combination with either dimercaprol or dimercaptosuccinic acid in an attempt to correlate changes in flavor-aversion conditioning to changes known to alter the toxicity of metal administration. Rats received po administration of either thallium sulfate or lead acetate given alone or in combination with either dimercaprol or dimercaptosuccinic acid after consuming saccharin. Three days later they were given the choice between consuming saccharin or water, and saccharin preferences were recorded. When compared to rats receiving either nothing or the vehicle, rats receiving either lead or thallium showed significant reductions in saccharin preferences (i.e., conditioned flavor aversions). Rats receiving lead acetate in combination with either of the two chelators displayed significantly reduced conditioned flavor aversions when compared to the aversions induced in rats receiving lead alone. Under the same conditions, there were no differences in the conditioned flavor aversions of rats receiving thallium only and those of rats receiving thallium in combination with either of the two chelators. Attenuation of the lead-induced conditioned flavor aversions was eliminated when chelator administration was delayed by 4 hr. This attenuation of lead-induced but not thallium-induced aversions by dimercaprol and dimercaptosuccinic acid demonstrates the sensitivity and selectivity of the flavor-aversion conditioning paradigm in characterizing metal-chelator interactions and is in agreement with clinical reports of effective chelation therapy in cases of lead but not thallium intoxication.