Reversal of gallium arsenide-induced suppression of the antibody response by a mixed disulfide metabolite of meso-2,3-dimercaptosuccinic acid.
Meso-2,3-dimercaptosuccinic acid (DMSA) has been demonstrated to be an effective chelator of lead, mercury and arsenic in humans and in rodent experiments. Studies involving cadmium exposure have typically shown DMSA to be less effective than 2,3-dimercapto-1-propanesulfonic acid, and this is possibly due to an inability of DMSA to cross cell membranes and bind intracellularly-bound metal ions. The present studies were designed to determine whether in vitro addition of DMSA could effectively reverse arsenic-induced immunosuppression in splenocytes exposed in vivo to gallium arsenide (GaAs; 200 mg/kg, intratracheally). In those investigations, DMSA (25-100 microM) was incapable of reversing suppression of the in vitro-generated antibody response induced by in vivo exposure to GaAs. Addition of the recently synthesized 2:1 mixed disulfide (L-cysteine-DMSA) metabolite of DMSA (0.1-100 microM) to cultures of splenocytes exposed in vitro to GaAs (50 microM) dose-dependently reversed GaAs-induced suppression of the antibody-forming cell response with no effect on the vehicle (complete media) response or on cell viability, indicating that the metabolite retained binding capacity. Unlike DMSA, however, addition of the 2:1 mixed disulfide metabolite to splenocyte cultures exposed in vivo to vehicle (0.05% Tween 80 in saline) or GaAs dose-dependently partially reversed GaAs-induced suppression. The reversal of suppression could not be attributed to cleavage of L-cysteine from the 2:1 mixed disulfide metabolite, as addition of equimolar concentrations of L-cysteine or L-cystine (0.2-200 microM) to in vitro generated antibody cultures of splenocytes exposed in vivo to vehicle or GaAs had no effect on the GaAs-induced suppression.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
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Burns
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Butterworth
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Munson
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D001151:Arsenic / Q000494:pharmacology*; D001152:Arsenicals; D003545:Cysteine / Q000494:pharmacology; D003553:Cystine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D005708:Gallium / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D012756:Sheep; D004113:Succimer / Q000378:metabolism / Q000494:pharmacology*
D001152:Arsenicals; C043055:gallium arsenide; D003553:Cystine; D005708:Gallium; D004113:Succimer; D003545:Cysteine; D001151:Arsenic