Metalloporphyrin Co(III)TMPyP ameliorates acute, sublethal cyanide toxicity in mice

The formation of Co(III)TMPyP(CN)(2) at pH 7.4 has been shown to be completely cooperative (α(H) = 2) with an association constant of 2.1 (±0.2) × 10(11). The kinetics were investigated by stopped-flow spectrophotometry and revealed a complicated net reaction exhibiting 4 phases at pH 7.4 under conditions where cyanide was in excess. The data suggest molecular HCN (rather than CN(-)) to be the attacking nucleophile around neutrality. The two slower phases do not seem to be present when cyanide is not in excess, and the other two phases have rates comparable to that observed for cobalamin, a known effective cyanide scavenger. Addition of bovine serum albumin (BSA) did not affect the cooperativity of cyanide binding to Co(III)TMPyP, only lowered the equilibrium constant slightly to 1.2 (±0.2) × 10(11) and had an insignificant effect on the observed rate. A sublethal mouse model was used to assess the effectiveness of Co(III)TMPyP as a potential cyanide antidote. The administration of Co(III)TMPyP to sodium cyanide intoxicated mice resulted in the time required for the surviving mice to right themselves from a supine position being significantly decreased (9 ± 2 min) compared to that of the controls (33 ± 2 min). All observations were consistent with the demonstrated antidotal activity of Co(III)TMPyP operating through a cyanide-binding (i.e., scavenging) mechanism.