Chelliah J, Smith J D, Fariss M W
Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0662.
Biochim Biophys Acta. 1994 May 18;1206(1):17-26. doi: 10.1016/0167-4838(94)90067-1.
The anticholinesterase properties of tetrahydroaminoacridine (THA, Tacrine), alpha-tocopheryl hemisuccinate (TS), and cholesteryl hemisuccinate (CS), given alone and in combination, were examined in vitro. Results from these studies indicate that: [1] THA is a potent inhibitor of acetylcholinesterase (AChE, IC50 of 0.40 microM) and butyrylcholinesterase (BChE, IC50 of 0.10 microM) with greatest inhibitory activity towards BChE; [2] TS and CS are weak inhibitors of BChE (IC50 of 100 microM and 168 microM, respectively) but potent inhibitors of ACHE (IC50 of 1.73 microM and 0.79 microM, respectively); [3] both TS and CS treatment in combination with THA significantly increased THA's anticholinesterase activity. The percentage AChE inhibition observed with this combination was often significantly greater than the sum of the individual values (synergistic). The addition of 0.5 microM CS or TS to an ACHE preparation reduced THA's IC50 value from 0.40 microM or 0.18 microM, respectively [4]; inhibition of AChE by THA, TS and CS are mixed non-competitive while THA inhibition of BChE is mixed non-competitive and TS and CS inhibition of BChE are simple non-competitive; and [5] inhibition of cholinesterases by TS and CS occurs immediately (50 to 75%), during the first 30 min of incubation (25 to 50%) and is dependent on the anionic charged portion of the molecule. In conclusion, our experimental data indicate that TS and CS are potent inhibitors of AChE activity and significantly potentiate the anticholinesterase activity of THA. Such potent and synergistic inhibition of AChE suggest that TS or CS, alone and in combination with THA, may prove beneficial in the treatment of organophosphate poisoning and Alzheimer's disease.
在体外研究了单独及联合给予的四氢氨基吖啶（THA，他克林）、α-生育酚半琥珀酸酯（TS）和胆固醇半琥珀酸酯（CS）的抗胆碱酯酶特性。这些研究结果表明：[1]THA是乙酰胆碱酯酶（AChE，IC50为0.40微摩尔）和丁酰胆碱酯酶（BChE，IC50为0.10微摩尔）的强效抑制剂，对BChE的抑制活性最强；[2]TS和CS是BChE的弱抑制剂（IC50分别为100微摩尔和168微摩尔），但却是ACHE的强效抑制剂（IC50分别为1.73微摩尔和0.79微摩尔）；[3]TS和CS与THA联合治疗均显著提高了THA的抗胆碱酯酶活性。该联合用药观察到的AChE抑制百分比通常显著高于各单独值之和（协同作用）。向ACHE制剂中添加0.5微摩尔的CS或TS分别使THA的IC50值从0.40微摩尔或0.18微摩尔降低[4]；THA、TS和CS对AChE的抑制作用为混合非竞争性，而THA对BChE的抑制作用为混合非竞争性，TS和CS对BChE的抑制作用为简单非竞争性；[5]TS和CS对胆碱酯酶的抑制在孵育的前30分钟内立即发生（50%至75%），随后（25%至50%），且取决于分子的阴离子带电部分。总之，我们的实验数据表明，TS和CS是AChE活性的强效抑制剂，并显著增强了THA的抗胆碱酯酶活性。这种对AChE的强效协同抑制表明，TS或CS单独以及与THA联合使用，可能在有机磷中毒和阿尔茨海默病的治疗中被证明是有益的。
