Inhibition of choline transport in erythrocytes by n-alkanols.
The choline transport system of erythrocytes is reversibly inhibited by ethanol, n-butanol, n-hexanol, n-octanol, and n-decanol, but not by n-dodecanol. Each methylene group in the alkyl chain contributes 560 cal/mol to the free energy of binding at the inhibitory site. Inhibition results from the cooperative binding of two molecules of an alcohol, judging by the Hill coefficient n of 1.7-1.9. The mechanism of inhibition is noncompetitive, and the partition of the carrier between inward-facing and outward-facing forms is unaffected by the alcohols; it follows that the four main carrier forms, the inner and outer free carrier, and the inner and outer carrier-substrate complex, are equally susceptible to inhibition. Hexanol and decanol accelerate the reaction of N-ethylmaleimide with a thiol group in the inner carrier channel, but ethanol and butanol, at concentrations that inhibit transport by 70%, do not. The disproportionate effects on substrate transport and the N-ethylmaleimide reaction are most simply explained as the direct result of binding of alcohol molecules in different regions of the carrier, rather than as the indirect result of a disturbance in the structure of the lipid bilayer induced by the alcohols.
Devés
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Department of Physiology and Biophysics, Faculty of Medicine, University of Chile, Santiago.
Krupka
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RM
D020001:1-Butanol; D020003:1-Octanol; D000438:Alcohols / Q000494:pharmacology*; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D000440:Butanols / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000737:chemistry; D002794:Choline / Q000037:antagonists & inhibitors* / Q000097:blood*; D004912:Erythrocytes / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D005233:Fatty Alcohols / Q000378:metabolism / Q000494:pharmacology; D000441:Hexanols / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D000442:Octanols / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D013816:Thermodynamics
D000438:Alcohols; D000440:Butanols; D002352:Carrier Proteins; D005233:Fatty Alcohols; D000441:Hexanols; D000442:Octanols; D000431:Ethanol; C036260:1-hexanol; C029383:n-decyl alcohol; D020001:1-Butanol; D002794:Choline; D020003:1-Octanol; D005033:Ethylmaleimide