In vitro influences of alcohols on mouse synaptosomes, and structure-activity relationships.
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.
Tanii
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Department of Hygiene, School of Medicine, Kanazawa University, Japan.
Zhang
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XP
Ohyashiki
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D000110:Acetylcholinesterase / Q000187:drug effects; D000438:Alcohols / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000187:drug effects; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects* / Q000201:enzymology
D000438:Alcohols; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D000254:Sodium-Potassium-Exchanging ATPase