Xia Yangliu, Pang Huilin, Dou Tongyi, Wang Ping, Ge Guangbo
Laboratory of Pharmacology & Toxicology, School of Life Science and Medicine, Dalian University of Technology Panjin 124221 China
Shanghai University of Traditional Chinese Medicines Shanghai 201203 China
RSC Adv. 2018 May 1;8(29):16278-16284. doi: 10.1039/c8ra01938j. eCollection 2018 Apr 27.
Catechol--methyltransferase (COMT) is a druggable biological target and COMT modulators have been widely applied in the treatment of various central and peripheral nervous system disorders. The interspecies differences of COMT were carefully investigated using 3-BTD (a newly developed fluorescent probe of COMT) methylation as the probe reaction, and liver S9 from humans and seven experimental animals including monkeys, dogs, mice, rats, minipigs, guinea pigs and New Zealand rabbits as the enzyme source. Metabolite profiling demonstrated that all the tested liver S9 samples from the different animals could catalyse 3-BTD methylation but displayed significant differences in reaction rate. Also, the differential effects of tolcapone (a potent inhibitor against COMT) on 3-BTD methylation among various species were observed. The apparent kinetic parameters and the maximum intrinsic clearances (Cl) for 3-BTD methylation in liver S9 from the different animals were determined, and the order of the Cl values for the formation of 3-BTD was RLS9 > DLS9 ≈ PLS9 > MLS9 > CyLS9 > RaLS9 > GpLS9 > HLS9. These findings are helpful for further exploring COMT-associated biological processes in animal models, as well as for developing therapeutic molecules that target COMT.
儿茶酚 - 甲基转移酶（COMT）是一个可成药的生物学靶点，COMT调节剂已广泛应用于各种中枢和外周神经系统疾病的治疗。使用3 - BTD（一种新开发的COMT荧光探针）甲基化作为探针反应，并以人和包括猴子、狗、小鼠、大鼠、小型猪、豚鼠和新西兰兔在内的七种实验动物的肝脏S9作为酶源，仔细研究了COMT的种间差异。代谢物谱分析表明，来自不同动物的所有测试肝脏S9样品都能催化3 - BTD甲基化，但反应速率存在显著差异。此外，还观察到托卡朋（一种强效COMT抑制剂）对不同物种间3 - BTD甲基化的不同影响。测定了不同动物肝脏S9中3 - BTD甲基化的表观动力学参数和最大内在清除率（Cl），3 - BTD形成的Cl值顺序为RLS9 > DLS9 ≈ PLS9 > MLS9 > CyLS9 > RaLS9 > GpLS9 > HLS9。这些发现有助于在动物模型中进一步探索与COMT相关的生物学过程，以及开发靶向COMT的治疗分子。
