Mechanism of perfluoroalkyl halide toxicity: catalysis of perfluoroalkylation by reduced forms of cobalamin (vitamin B12).
Perfluoroalkyl halides (PFHs) are synthetic products widely used in various fields. Perfluorooctyl bromide (PFB) is used in medicine as a component of blood substitutes and for artificial lung ventilation. In both cases, it is considered a completely inert compound acting as a solvent for oxygen. However, there are many reports of PFH-induced intoxication, including lethal cases. Mechanisms underlying toxic effects of this compound remain unknown. In this study, we demonstrate that the reduced form of cobalamin (vitamin B12) typical for B12-dependent enzymes can catalyze the reactions of perfluoroalkylation, aromatic substitution, or addition by double bonds. Synthesis of perfluoro derivatives from PFHs during catalysis by cob(I)alamin-like super nucleophiles is a new possible mechanism responsible for in vivo formation of highly toxic compounds from "chemically inert" substances widely used in medicine. Catalytic perfluoroalkylation might possibly contribute to nitric oxide depletion and modulation of activity of guanylate cyclase, cytochromes, NO-synthases, and other heme-containing proteins.
Beda
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NV
Institute of Molecular Genetics, Russian Academy of Sciences, Moscow 123182, Russia. beda@img.ras.ru
Nedospasov
A A
AA
D000478:Alkylation / Q000187:drug effects; D002384:Catalysis / Q000187:drug effects; D005461:Fluorine / Q000737:chemistry; D006846:Hydrocarbons, Halogenated / Q000737:chemistry* / Q000633:toxicity*; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry; D010084:Oxidation-Reduction; D014805:Vitamin B 12 / Q000737:chemistry* / Q000494:pharmacology
D006846:Hydrocarbons, Halogenated; D005461:Fluorine; D009569:Nitric Oxide; D014805:Vitamin B 12