Verschoyle R D, Brown A W, Ray D E, Bird I
Toxicol Appl Pharmacol. 1987 Jun 30;89(2):175-82. doi: 10.1016/0041-008x(87)90038-x.
The trihalogenated imidazoles, trichloroimidazole (TCI), tribromoimidazole (TBI), and triiodoimidazole (TII), are in vitro uncouplers of oxidative phosphorylation with similar activities. Although TCI and TBI are also uncouplers in vivo, some doubt exists for TII, which is much less toxic and produces atypical signs of poisoning. Dibromo- and monobromoimidazole do not uncouple oxidative phosphorylation either in vitro or in vivo. Dosing of TCI and TBI to rats resulted within 24-48 hr in neuronal necrosis within the CNS involving the vestibular nucleus, red nucleus, and outer parietal neocortex and ataxia of the hindlimbs. However, no neuronal necrosis or ataxia was observed after dosing of TII to rats, even when given at doses four times greater than for either TCI or TBI, resulting in much higher brain concentrations. Although TBI was equitoxic to rats, mice, hamsters, and gerbils, CNS damage and ataxia were observed only in the rat, even though comparable brain concentrations of TBI were found in the gerbil. Measurement of the concentration of TBI in the dissected rat brain gave no indication of localized concentrations of compound in the areas associated with neuronal damage. Doses of TBI and the classical uncoupler 3,5-dinitro-o-cresol (DNOC), matched for whole body O2 consumption, caused comparable changes in rat brain blood flow although DNOC does not cause brain damage. Changes in blood flow were not restricted to those brain areas susceptible to damage. Thus, although we were unable to completely dissociate CNS damage from uncoupling of oxidative phosphorylation produced by TBI and TCI in the rat, it is unlikely that such damage is primarily related to the uncoupling ability of these compounds.
三卤代咪唑类化合物，三氯咪唑（TCI）、三溴咪唑（TBI）和三碘咪唑（TII），是具有相似活性的体外氧化磷酸化解偶联剂。虽然TCI和TBI在体内也是解偶联剂，但对于TII存在一些疑问，TII的毒性小得多，且产生非典型中毒症状。二溴咪唑和一溴咪唑在体外和体内均不解偶联氧化磷酸化。给大鼠注射TCI和TBI后，在24 - 48小时内，中枢神经系统（CNS）出现神经元坏死，累及前庭核、红核和外侧顶叶新皮质，后肢共济失调。然而，给大鼠注射TII后，即使给予比TCI或TBI大四倍的剂量，导致脑内浓度高得多，也未观察到神经元坏死或共济失调。虽然TBI对大鼠、小鼠、仓鼠和沙鼠的毒性相同，但仅在大鼠中观察到中枢神经系统损伤和共济失调，尽管在沙鼠中发现了与大鼠相当的脑内TBI浓度。测定解剖后的大鼠脑中TBI的浓度，未发现该化合物在与神经元损伤相关区域有局部浓度升高。与全身耗氧量匹配的TBI剂量和经典解偶联剂3,5 - 二硝基邻甲酚（DNOC）剂量，引起大鼠脑血流的可比变化，尽管DNOC不会导致脑损伤。血流变化并不局限于那些易受损伤的脑区。因此，虽然我们无法在大鼠中将中枢神经系统损伤与TBI和TCI产生的氧化磷酸化解偶联完全分开，但这种损伤不太可能主要与这些化合物的解偶联能力有关。
