Scheibel L W, Adler A, Trager W
Proc Natl Acad Sci U S A. 1979 Oct;76(10):5303-7. doi: 10.1073/pnas.76.10.5303.
Plasmodium falciparum in culture grows optimally at 3% oxygen. Oxygen levels down to 0.5% still support growth, but anaerobic conditions do not. These findings, and the absence of the Krebs cycle in Plasmodium, suggested that in this organism oxygen may not function in electron transport but rather may act through metalloprotein oxygenases. Tetraethylthiuram disulfide (Antabuse, disulfiram) and its reduction product diethyldithiocarbamate inhibit many metalloprotein oxygenases and have a lipid/H2O partition coefficient and high binding constant for metal ions, favoring selective toxicity to the malaria parasite. These compounds exhibited active antimalarial effects in vitro in concentrations down to 0.1 microgram/ml, the lowest level tested. Tetraethylthiuram disulfide at a level as low as 1 microgram/ml inhibited parasite glycolysis with no effect on glycolysis of normal erythrocytes. Erythrocytes pretreated with this drug at 10 microgram/ml did not support growth of the parasite.
恶性疟原虫在培养时，在3%氧气浓度下生长最佳。氧气浓度降至0.5%仍能支持其生长，但厌氧条件则不行。这些发现，以及疟原虫中不存在三羧酸循环，表明在这种生物体中，氧气可能不在电子传递中起作用，而是可能通过金属蛋白加氧酶起作用。二硫化四乙秋兰姆（戒酒硫、双硫仑）及其还原产物二乙基二硫代氨基甲酸盐可抑制许多金属蛋白加氧酶，并且具有脂质/水分配系数以及对金属离子的高结合常数，有利于对疟原虫产生选择性毒性。这些化合物在体外浓度低至0.1微克/毫升（测试的最低水平）时表现出抗疟活性。低至1微克/毫升的二硫化四乙秋兰姆可抑制寄生虫糖酵解，而对正常红细胞的糖酵解无影响。用10微克/毫升这种药物预处理的红细胞不支持寄生虫的生长。
