The inhibition of a membrane-bound enzyme as a model for anaesthetic action and drug toxicity.
The inhibition of the membrane-bound enzyme cytochrome c oxidase by aliphatic n-alcohols and other neutral organic compounds was studied as a model for anaesthetic action and drug toxicity. The n-alcohols (C1 to C14) displayed a variation in inhibition constant of over 500,000-fold. The inhibition constants correlated well with the number of carbon atoms in the n-alcohols and also their n-octanol/water partition coefficients. General anaesthetic potency is known to be similarly well correlated with octanol/water partition coefficients. The free-energy change for transferring a methylene group of the n-alcohol to the more hydrophobic environment bound to the enzyme is similar to that for transferring a methylene group from water to pure alcohol. These results are consistent with the n-alcohols inhibiting by binding to an octanol-like environment on the enzyme or the protein/phospholipid interface. Neither negatively charged carboxylates nor positively charged amine analogues were observed to cause any inhibition, indicating that this postulated binding site may be uncharged. Inhibition of cytochrome c oxidase by n-alcohols was also demonstrated in both bovine heart and rat liver sonicated submitochondrial fragments.
Hasinoff
B B
BB
Memorial University of Newfoundland, Department of Chemistry, Canada.
Davey
J P
JP
D000438:Alcohols / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D006736:Horses; D007700:Kinetics; D008566:Membranes / Q000201:enzymology; D008954:Models, Biological; D012995:Solubility; D013367:Submitochondrial Particles / Q000201:enzymology; D014116:Toxicology
D000438:Alcohols; D000777:Anesthetics; D003576:Electron Transport Complex IV