Alcohols Inhibit Glucose Transporters Noncompetitively at a Constant Membrane Concentration According to Lipid Theory

Various chemicals obey the Meyer-Overton correlation, where the potency increases exponentially with the partition coefficient. However, the principle remains controversial. While the protein theory is based on the competitive inhibition of the nonmembrane protein models by alcohols and anesthetics, this study conducted kinetic analysis using the yeast hexose transporter Hxt2, a functional membrane protein. Saturated alcohols (C₂-C₈) inhibited Hxt2 noncompetitively and drug efflux according to the correlation. Thus, the alcohols interacting nonspecifically with the membrane affect various membrane targets and inhibit Hxt2 from the lateral membrane-facing side, supporting the lipid theory. The alcohols exerted similar inhibitory potencies at a constant membrane concentration (C_m), regardless of chain length. Consequently, the principle of the Meyer-Overton correlation is the maintenance of a constant C_m, whereas administered aqueous concentrations (C_w) merely decrease with the partition coefficients. Therefore, intracellular C_m, rather than extracellular C_w, provides an accurate measure of the chemical potency, offering a framework for drug repositioning.