Abstract:
The aerotoxic syndrome has been associated with exposure to tricresyl phosphate (TCP), which is used as additive in hydraulic fluids and engine lubricants. The toxic metabolite 2-(2-cresyl)-4H-1,3,2-benzodioxaphosphorin-2-oxide (CBDP) is formed from the TCP isomer tri-ortho-cresyl phosphate (TOCP) in vivo and is known to react with the active site serine in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) resulting in the inhibition of the enzymes. Previous in vitro studies showed pronounced species differences in the inhibition kinetics of cholinesterases by organophosphorus compounds (OP), which must be considered in the development of relevant animal models for the investigation of OP poisoning and the aerotoxic syndrome. The present study was designed to investigate the inhibition kinetics of human, Cynomolgus monkey, pig, mini pig, guinea pig, mouse, and rat AChE as well as BChE by CBDP under standardized conditions. There were similar rate constants for the inhibition (ki) of human, Cynomolgus monkey and mouse AChE by CBDP. In contrast, the ki values obtained for guinea pig, mini pig, pig, and rat AChE were 2.8- to 5.9-fold lower than that of human AChE. The results of the present study confirmed CBDP as one of the most potent inhibitors of human BChE, indicating a ki value of 3.24 ± 0.33 ×108M-1min-1, which was about 1,140-fold higher than that of human AChE. Accordingly, a markedly more pronounced inhibition rate of BChE from the species guinea pig, mini pig, pig, rat, Cynomolgus monkey, and mouse by CBDP was found as compared to those of AChE from the respective sources, indicating 2.0- to 89.6-fold higher ki values.
摘要:
气毒性综合征与暴露于磷酸三甲苯酯(TCP)有关,用作液压油和发动机润滑油中的添加剂。有毒代谢物2-(2-甲苯基)-4H-1,3,2-苯并二氧杂磷-2-氧化物(CBDP)由TCP异构体三-邻甲苯基磷酸酯(TOCP)在体内形成,并且已知与活性位点丝氨酸反应乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE),从而抑制酶。先前的体外研究表明,有机磷化合物(OP)对胆碱酯酶的抑制动力学存在明显的物种差异,在开发相关动物模型以研究OP中毒和气毒性综合征时必须考虑这一点。本研究旨在研究人类的抑制动力学,食蟹猴,猪,迷你猪,豚鼠,鼠标,在标准化条件下通过CBDP和大鼠AChE以及BChE。人的抑制(ki)有相似的速率常数,食蟹猴和小鼠AChE通过CBDP。相比之下,获得的豚鼠的ki值,迷你猪,猪,大鼠AChE比人AChE低2.8至5.9倍。本研究的结果证实CBDP是人类BChE最有效的抑制剂之一。表明ki值为3.24±0.33×108M-1min-1,比人AChE大约1,140倍。因此,豚鼠对BChE的抑制率明显更明显,迷你猪,猪,rat,食蟹猴,与来自各自来源的AChE相比,通过CBDP发现了小鼠,表示ki值大2.0到89.6倍。