Tanii H, Zhang X P, Ohyashiki T
Department of Hygiene, School of Medicine, Kanazawa University, Japan.
Arch Toxicol. 1995;69(9):617-23. doi: 10.1007/s002040050222.
Little information is available on the structure-central nervous system membrane toxicity relationship of alcohols. The purpose of the present study was to study in vitro influence of alcohols (n = 20) on the activity of the toxic indicator Na+/K(+)-adenosine triphosphatase (Na+/K(+)-ATPase) and acetylcholinesterase (AchE), and membrane fluidity in mouse brain synaptosomes, in terms of the structure-activity relationship. The potency of inhibition for the enzymes (IC50) and the potency of increasing membrane fluidity (IC12.5) were determined experimentally, and n-octanol/water partition coefficient (P) and the steric constant Taft Es are cited from the literature. Regression analysis revealed that log 1/IC50 for Na+/K(+)-ATPase is a function of log P and Taft Es. The situation was true for AchE activity. The results indicate that the hydrophobicity expressed as log P and the steric effect of the alcohols play an important role in inhibiting both enzyme activities. A linear relationship between log 1/IC12.5 for membrane fluidity and log P is shown, indicating a significant effect of the alcohols on membrane fluidity. Based on these results, it is suggested that the alcohols inhibit the Na+/K(+)-ATPase and AchE activity through a direct action on the enzymes and/or through changing the membrane fluidity.
关于醇类与中枢神经系统膜毒性关系的结构，目前所知信息甚少。本研究的目的是根据构效关系，研究20种醇类对小鼠脑突触体中毒性指标钠钾腺苷三磷酸酶（Na⁺/K⁺-ATP酶）和乙酰胆碱酯酶（AchE）活性以及膜流动性的体外影响。通过实验测定酶抑制效力（IC50）和增加膜流动性的效力（IC12.5），正辛醇/水分配系数（P）和空间常数塔夫脱Es引自文献。回归分析表明，Na⁺/K⁺-ATP酶的log 1/IC50是log P和塔夫脱Es的函数。AchE活性情况也是如此。结果表明，以log P表示的疏水性和醇类的空间效应在抑制两种酶活性中起重要作用。膜流动性的log 1/IC12.5与log P之间呈线性关系，表明醇类对膜流动性有显著影响。基于这些结果，提示醇类通过直接作用于酶和/或通过改变膜流动性来抑制Na⁺/K⁺-ATP酶和AchE活性。
