Mechanisms of Drug Toxicity Group, Pharmaceutical Sciences Institute, Aston University, Aston Triangle, Birmingham, B4 7ET, UK.
Environ Toxicol Pharmacol. 1999 Mar;7(1):59-65. doi: 10.1016/s1382-6689(98)00055-6.
We have investigated the toxicity of a series of 2-pyridylcarboxamidrazones in vitro using a rat liver metabolism system as well as human erythrocytes and mononuclear leucocytes (MNL) as target cells. Of the seven derivatives and four precursors tested, only minimal (<2.3%) metabolism-mediated methaemoglobin was formed by two analogues. However, one of these, a naphthylidene 2-pyridylcarboxamidrazone derivative (compound III), was also directly toxic to human MNLs. This toxicity was partially attenuated by the rat metabolising system and incubation of diethyldithiocarbamate or cimetidine together with compound III and the rat metabolising system suppressed the metabolism-dependent detoxification. This indicated that cytochrome P-450-mediated biotransformation of compound III was preventing its direct toxicity to the MNL. Of the seven derivatives tested, six were low in toxicity to MNL directly and in the presence of a metabolising system. The two compounds which were the most potent anti-mycobacterially, the dimethylpropyl and dimethylethyl benzylidene amidrazone derivatives, were also the least toxic to MNL and erythrocytes. This amidrazone series has shown promise for future development as antituberculosis drugs.
我们使用大鼠肝代谢系统以及人红细胞和单核白细胞（MNL）作为靶细胞，研究了一系列 2-吡啶甲酰胺腙的体外毒性。在所测试的七个衍生物和四个前体中，只有两种类似物通过代谢介导形成了最小量（<2.3%）的高铁血红蛋白。然而，其中一种萘基亚甲基 2-吡啶甲酰胺腙衍生物（化合物 III）也对人 MNL 具有直接毒性。这种毒性部分被大鼠代谢系统减弱，并且二乙基二硫代氨基甲酸盐或西咪替丁与化合物 III 和大鼠代谢系统一起孵育可抑制依赖代谢的解毒作用。这表明细胞色素 P-450 介导的化合物 III 的生物转化防止了其对 MNL 的直接毒性。在所测试的七个衍生物中，有六个直接对 MNL 和代谢系统具有低毒性。两种在抗分枝杆菌方面最有效的化合物，即二甲基丙基和二甲基乙基苄基亚甲基腙衍生物，对 MNL 和红细胞的毒性也最小。该腙系列具有作为抗结核药物进一步开发的前景。
