Chemistry and enzymology of vitamin B12.

The organic compounds of cobalt(III)

Cis, trans, and metal effects in transition metal porphyrins

Context. Cyanide is a rapidly acting cellular poison, primarily targeting cytochrome c oxidase, and is a common occupational and residential toxin, mostly via smoke inhalation. Cyanide is also a potential weapon of mass destruction, with recent credible threats of attacks focusing the need for better treatments, as current cyanide antidotes are limited and impractical for rapid deployment in mass casualty settings. Objective. We have used mouse models of cyanide poisoning to compare the efficacy of cobinamide (Cbi), the precursor to cobalamin (vitamin B12), to currently approved cyanide antidotes. Cbi has extremely high affinity for cyanide and substantial solubility in water. Materials and Methods. We studied Cbi in both an inhaled and intraperitoneal model of cyanide poisoning in mice. Results. We found Cbi more effective than hydroxocobalamin, sodium thiosulfate, soldium nitrite, and the combination of sodium thiosulfate–sodium nitrite in treating cyanide poisoning. Compared to hydroxocobalamin, Cbi wa...

Cobinamide is superior to other treatments in a mouse model of cyanide poisoning.

Cyanide is a highly toxic agent that inhibits mitochondrial cytochrome-c oxidase, thereby depleting cellular ATP. It contributes to smoke inhalation deaths in fires and could be used as a weapon of mass destruction. Cobalamin (vitamin B12) binds cyanide with a relatively high affinity and is used in Europe to treat smoke inhalation victims. Cobinamide, the penultimate compound in cobalamin biosynthesis, binds cyanide with about 10(10) greater affinity than cobalamin, and we found it was several-fold more effective than cobalamin in (i) reversing cyanide inhibition of oxidative phosphorylation in mammalian cells; (ii) rescuing mammalian cells and Drosophila melanogaster from cyanide toxicity; and (iii) reducing cyanide inhibition of Drosophila Malpighian tubule secretion. Cobinamide could be delivered by oral ingestion, inhalation, or injection to Drosophila, and it was as effective when administered up to 5 mins post-cyanide exposure as when given pre-exposure. We conclude that cobinamide is an effective cyanide detoxifying agent that has potential use as a cyanide antidote, both in smoke inhalation victims and in persons exposed to cyanide used as a weapon of mass destruction.

N. J. Vanston

Papers

1196. The chemistry of vitamin B12. Part IV. The thermodynamic trans-effect

The chemistry of vitamin B 12. IV. The thermodynamic trans-effect.