Cyanide antagonism with carrier erythrocytes and organic thiosulfonates.
Previous studies reported that resealed erythrocytes containing rhodanese (CRBC) and NA2S2O3 rapidly metabolize cyanide to the less toxic thiocyanate both in vitro and in vivo. This provided a new conceptual approach to prevent and treat cyanide intoxication. Although the rhodanese-containing carrier cells with thiosulfate as the sulfur donor were efficacious, this approach has potential disadvantages, as thiosulfate has limited penetration of cell membrane and product inhibition of rhodanese can occur due to inorganic sulfite accumulation. In order to circumvent substrate limitation and product inhibition by sodium thiosulfate, organic thiosulfonates were explored. These thiosulfonates have higher lipid solubility than thiosulfate and therefore can replenish the depleted sulfur donor, as they can readily penetrate cell membranes. Also, product inhibition of rhodanese is less apt to occur. This change in sulfur donors should greatly enhance cyanide detoxication, replenish the sulfur donor, and minimize product inhibition of rhodanese. Present studies demonstrate the enhanced efficacy of exogenous organic thiosulfonates over sodium thiosulfate in the CRBC antidotal system to detoxify the lethal effects of cyanide either alone or in combinations with exogenously administered NaNO2. Murine carrier erythrocytes containing purified bovine liver rhodanese were administered intravenously into male Balb/C mice. Subsequently, butanethiosulfonate (BTS) or Na2S2O3 (ip), and NaNO2 (sc) were co-administered prior to KCN (sc). Potency ratios, derived from the LD50 values, were compared in groups of mice treated with CRBC-Na2S2O3 or CRBC-BTS either alone or in combination with NaNO2.(ABSTRACT TRUNCATED AT 250 WORDS)
Petrikovics
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Department of Medical Pharmacology and Toxicology, Texas A&M University, College Station 77843-1114.
Cannon
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McGuinn
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Pei
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Pu
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Lindner
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Way
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JL
D000818:Animals; D000931:Antidotes / Q000008:administration & dosage* / Q000494:pharmacology*; D003486:Cyanides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004337:Drug Carriers; D004912:Erythrocytes / Q000737:chemistry / Q000201:enzymology*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012977:Sodium Nitrite / Q000008:administration & dosage / Q000494:pharmacology; D013884:Thiosulfate Sulfurtransferase / Q000008:administration & dosage* / Q000494:pharmacology*; D013885:Thiosulfates / Q000008:administration & dosage / Q000494:pharmacology; D013886:Thiosulfonic Acids / Q000008:administration & dosage* / Q000633:toxicity*
D000931:Antidotes; D003486:Cyanides; D004337:Drug Carriers; D013885:Thiosulfates; D013886:Thiosulfonic Acids; D013884:Thiosulfate Sulfurtransferase; D012977:Sodium Nitrite