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ORIGINAL RESEARCH ARTICLE

Cyanide Detoxification by the Cobalamin Precursor Cobinamide

Kate E. Broderick^*, Prasanth Potluri, Shunhui Zhuang^*, Immo E. Scheffler, Vijay S. Sharma^*, Renate B. Pilz^*, and Gerry R. Boss^*,,1

^* Departments of Medicine and Biology and Cancer Center, University of California, San Diego, La Jolla, California 92093-0652

To whom requests for reprints should be addressed at ¹ University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0652. E-mail: gboss{at}ucsd.edu

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 10¹⁰ 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.

Key Words: cyanide • cobalamin • cobinamide • Chinese hamster fibroblasts • Drosophila melanogaster

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