Department of Environmental and Occupational Health, Graduate School of Public Health, The University of Pittsburgh, 100 Technology Drive, Pittsburgh, Pennsylvania 15219, United States.
Chem Res Toxicol. 2012 Dec 17;25(12):2678-86. doi: 10.1021/tx300327v. Epub 2012 Dec 3.
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.
在 pH 值为 7.4 时，已证明 Co(III)TMPyP(CN)(2) 的形成完全具有协同性（α(H) = 2），其缔合常数为 2.1（±0.2）×10(11)。动力学研究采用停流分光光度法进行，在 pH 值为 7.4 时，氰化物过量的条件下，反应呈现出复杂的净反应，表现出 4 个阶段。数据表明，在中性条件下，攻击亲核试剂为分子 HCN（而不是 CN(-)）。当氰化物不过量时，似乎不存在两个较慢的阶段，而另外两个阶段的速率与钴胺素相当，钴胺素是一种已知的有效氰化物清除剂。添加牛血清白蛋白 (BSA) 不会影响氰化物与 Co(III)TMPyP 结合的协同性，仅略微降低平衡常数至 1.2（±0.2）×10(11)，并对观察到的速率影响不大。使用亚致死性小鼠模型来评估 Co(III)TMPyP 作为潜在氰化物解毒剂的效果。将 Co(III)TMPyP 给予氰化钠中毒的小鼠，与对照组（33±2 分钟）相比，幸存小鼠从仰卧位置自行翻身所需的时间明显缩短（9±2 分钟）。所有观察结果都与 Co(III)TMPyP 通过氰化物结合（即清除）机制发挥解毒作用的实验结果一致。
