Carr A W, McCracken R O, Stillwell W H
Department of Biology, Indiana University-Purdue University, Indianapolis 46202-5132.
J Parasitol. 1993 Apr;79(2):198-204.
The uncoupling activity of a narrow-spectrum benzimidazole anthelmintic triclabendazole (TCZ, 6-chloro-5-[2,3-dichlorophenoxy]-2-methylthio-benzimidazole) and its 2 principal metabolites triclabendazole sulfoxide (TCZ sulfoxide, 6-chloro-5-[2,3-dichlorophenoxy]-2-methylsulfinyl-benzimidazole) and triclabendazole sulfone (TCZ sulfone, 6-chloro-5-[2,3-dichlorophenoxyl]-2methylsulfonyl- benzimidazole) has been determined using rat liver mitochondria. With glutamate or succinate as the mitchondrial substrate, and the respiratory control index (RCI) as an indicator of uncoupling activity, we found that TCZ and its 2 main metabolites were uncouplers of oxidative phosphorylation at micromolar concentrations. The rank order of in vitro activity was TCZ sulfone > TCZ sulfoxide > TCZ. Structure-activity relationship studies revealed that the electron-withdrawing power of the substituent in the 2-position was the principal determinant of mitochondrial uncoupling activity. Correlation techniques were used to assess the strength of the relationship between the ability of TCZ and its metabolites to uncouple oxidative phosphorylation and their ability to lower the electrical resistance of planar bimolecular lipid membranes. A log-log plot of RCI I50 vs. resistance effective concentration (REC I50) gave a linear fit with a correlation coefficient (r) of 0.98; an r of 0.98 indicates a high positive relationship between the ability of these fasciolicides to uncouple oxidative phosphorylation and their ability to lower electrical resistance. These findings are consistent with the view that TCZ and its sulfoxide and sulfone metabolites are lipophilic protonophoric uncouplers of rat liver mitochondrial oxidative phosphorylation.
已使用大鼠肝线粒体测定了窄谱苯并咪唑驱虫药三氯苯达唑（TCZ，6-氯-5-[2,3-二氯苯氧基]-2-甲硫基苯并咪唑）及其2种主要代谢产物三氯苯达唑亚砜（TCZ亚砜，6-氯-5-[2,3-二氯苯氧基]-2-甲亚磺酰基苯并咪唑）和三氯苯达唑砜（TCZ砜，6-氯-5-[2,3-二氯苯氧基]-2-甲磺酰基苯并咪唑）的解偶联活性。以谷氨酸或琥珀酸作为线粒体底物，并以呼吸控制指数（RCI）作为解偶联活性的指标，我们发现TCZ及其2种主要代谢产物在微摩尔浓度下是氧化磷酸化的解偶联剂。体外活性的顺序为TCZ砜＞TCZ亚砜＞TCZ。构效关系研究表明，2-位取代基的吸电子能力是线粒体解偶联活性的主要决定因素。使用相关技术评估TCZ及其代谢产物解偶联氧化磷酸化的能力与其降低平面双分子脂质膜电阻的能力之间关系的强度。RCI I50与电阻有效浓度（REC I50）的对数-对数图给出了线性拟合，相关系数（r）为0.98；r为0.98表明这些杀片形吸虫剂解偶联氧化磷酸化的能力与其降低电阻的能力之间存在高度正相关。这些发现与以下观点一致，即TCZ及其亚砜和砜代谢产物是大鼠肝线粒体氧化磷酸化的亲脂性质子载体解偶联剂。
