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.
Research Article|February 15 1989
The inhibition of a membrane-bound enzyme as a model for anaesthetic action and drug toxicity
B B Hasinoff;
Biochem J (1989) 258 (1): 101-107.
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B B Hasinoff, J P Davey; The inhibition of a membrane-bound enzyme as a model for anaesthetic action and drug toxicity. Biochem J 15 February 1989; 258 (1): 101–107. doi: https://doi.org/10.1042/bj2580101
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