Department of Environmental and Occupational Health, Graduate School of Public Health , The University of Pittsburgh , 130 DeSoto Street , Pittsburgh , Pennsylvania 15219 , United States.
Chem Res Toxicol. 2020 Feb 17;33(2):594-603. doi: 10.1021/acs.chemrestox.9b00422. Epub 2020 Jan 23.
Three cobalt-containing macrocyclic compounds previously shown to antagonize cyanide toxicity have been comparatively evaluated for the amelioration of sublethal azide toxicity in juvenile (7-8 weeks) Swiss-Webster mice. The lowest effective doses were determined for hydroxocobalamin, a cobalt porphyrin, and a cobalt-Schiff base macrocycle by giving the antidotes 5 min prior to the toxicant, 27 mg (415 μmol) /kg sodium azide. Both male and female mice were evaluated for their response to the toxicant as well as the antidotes, and no significant differences were noted once weight differences were taken into account. Two of the three compounds significantly decreased the recovery time of azide-intoxicated mice at 10 min after the administration of sodium azide, as determined by a behavioral test (pole climbing). Additionally, azide was determined to cause a several degree drop (∼3 °C) in measured tail temperature, and warming the mice led to a more rapid recovery. The mice were also shown to recover more rapidly when given sodium nitrite, 24 mg (350 μmol)/kg, 5 min after the toxicant; this treatment also suppressed the azide-induced tail temperature decrease. Electron paramagnetic resonance (EPR) measurements of mouse blood treated with sodium azide demonstrated the presence of nitrosylhemoglobin at levels of 10-20 μM which persisted for ∼300 min. The presence of the methemoglobin azide adduct was also detected by EPR at a maximum level of ∼300 μM, but these signals disappeared around 200 min after the administration of azide. The treatment of mice with N sodium azide proved that the nitrosylhemoglobin was a product of the administered azide by the appearance of a two-line hyperfine (due to the N) in the EPR spectrum of mouse blood.
三种先前被证明能拮抗氰化物毒性的含钴大环化合物，已被用于比较评价它们对亚致死剂量叠氮化物毒性的改善作用，实验对象为幼鼠（7-8 周龄）瑞士-韦伯斯特小鼠。通过在给予毒物前 5 分钟给予解毒剂，确定了羟钴胺（一种钴卟啉）和钴席夫碱大环化合物的最低有效剂量，所用的毒物是 27 mg（415 μmol）/kg 的叠氮化钠。评价了雄性和雌性小鼠对毒物以及解毒剂的反应，考虑到体重差异后，没有发现显著差异。在给予叠氮化钠后 10 分钟，通过行为测试（爬杆），两种化合物中的两种可显著降低被叠氮化物中毒的小鼠的恢复时间。此外，叠氮化物会导致测量的尾巴温度下降几度（约 3°C），而给老鼠加热会导致更快的恢复。当给予亚硝酸钠，24 mg（350 μmol）/kg，5 分钟后，老鼠也能更快地恢复，这种治疗方法还抑制了叠氮化物引起的尾巴温度下降。用电子顺磁共振（EPR）测量用叠氮化钠处理的小鼠血液，证明存在浓度为 10-20 μM 的亚硝酰血红蛋白，持续约 300 分钟。EPR 还检测到最大浓度约为 300 μM 的高铁血红蛋白叠氮化物加合物，但这些信号在给予叠氮化物后约 200 分钟后消失。用 N 亚硝酸钠处理小鼠，证明了 EPR 光谱中出现的两条线超精细（由于 N），亚硝酰血红蛋白是给予的叠氮化物的产物。
