Lock E A
Chem Biol Interact. 1979;28(1):35-46. doi: 10.1016/0009-2797(79)90112-1.
2'-Chloro-2,4-dinitro-5',6-di(trifluoromethyl)diphenylamine (CDTD) is a potent uncoupler of oxidative phosphorylation in isolated rat liver or brain mitochondria. The concentration of CDTD causing 50% uncoupling in vitro is dependent on the mitochdonrial protein concentration and is 2 nM at 0.9 mg protein/ml for rat liver mitochondria. Oxidative phosphorylation can be restored to CDTD uncoupled liver mitochondria by the addition of a 10 000-fold molar excess of bovine serum albumin to DCTD. Rats given a lethal dose (7.0 mumol/kg) of CDTD intrapertioneally show signs of toxicity typical of uncoupling agents. Mitochondria isolated from the livers of these rats show almost complete inhibition of ATP synthesis and mitochondria obtained from the livers of rats at various times after a single oral dose show maximal inhibition of ATP synthesis 4 h after dosing with complete recovery by about 24 h. A single oral administration of 58 mumol/kg or above, but not intraperitoneal injection, of CDTD into rats produced an increase in the water content of the brain and spinal cord. The additional fluid has been shown to contain Na+ ions. The increase in cerebral fluid is dose related, no effect being seen at 23 mumol/kg. This extra fluid is thought to be responsible for the hind limb weakness observed in these rats. These observations suggest that there are two facets to CDTD toxicity: early deaths (within 2 h), which appear to be due to uncoupling of oxidative phosphorylation, and delayed deaths, 2--3 days after dosing which are probably related to an increase in fluid in the brain and spinal cord.
2'-氯-2,4-二硝基-5',6-二（三氟甲基）二苯胺（CDTD）是分离的大鼠肝脏或脑线粒体中氧化磷酸化的有效解偶联剂。在体外引起50%解偶联的CDTD浓度取决于线粒体蛋白浓度，对于大鼠肝脏线粒体，在蛋白浓度为0.9mg/ml时为2nM。向解偶联的肝脏线粒体中加入摩尔过量10000倍的牛血清白蛋白，可使氧化磷酸化恢复。腹腔注射致死剂量（7.0μmol/kg）的CDTD的大鼠表现出解偶联剂典型的毒性迹象。从这些大鼠肝脏分离的线粒体显示ATP合成几乎完全受到抑制，单次口服给药后不同时间从大鼠肝脏获得的线粒体在给药后4小时显示ATP合成最大抑制，约24小时后完全恢复。向大鼠单次口服58μmol/kg或更高剂量（但不是腹腔注射）的CDTD会导致脑和脊髓含水量增加。已证明额外的液体含有Na+离子。脑脊液增加与剂量相关，在23μmol/kg时未见影响。这种额外的液体被认为是这些大鼠后肢无力的原因。这些观察结果表明，CDTD毒性有两个方面：早期死亡（2小时内），似乎是由于氧化磷酸化解偶联；延迟死亡，给药后2至3天，可能与脑和脊髓中的液体增加有关。
