Biology subjects

Uesono, Y.

Publications and source records attributed to Uesono, Y..

3 recordsLinked to original sources

bioRxiv2025

Alcohols inhibit glucose transporters noncompetitively at a constant membrane concentration according to lipid theory

Various chemicals obey the Meyer-Overton correlation, in which potency increases exponentially with the partition coefficient. However, the principle remains unclear because of controversy between the lipid and protein theories. As the protein theory is based on the competitive inhibition of the non-membrane protein luciferase by alcohols and anesthetics, kinetic analysis was conducted on yeast hexose transporter Hxt2, a membrane protein. n-Alcohols (C2-C8) inhibited Hxt2 noncompetitively and drug efflux according to the correlation. Thus, the alcohols interacting nonspecifically with membrane affect various membrane targets and inhibit Hxt2 from the lateral membrane-facing side, thereby supporting the lipid theory. The alcohols exerted similar potencies at a constant membrane concentration (Cm), regardless of the chain length. Consequently, the principle of the Meyer-Overton correlation is the maintenance of a constant Cm, whereas administered aqueous concentrations (Cw) only decrease with their partition coefficients. Intracellular Cm, but not extracellular Cw, provides an accurate measure of chemical potency.

pharmacology and toxicology↗

bioRxiv2023

Establishment of the Meyer-Overton correlation in an artificial membrane without protein

BackgroundThe potency of anesthetics with various structures increases exponentially with lipophilicity, which is the Meyer-Overton (MO) correlation discovered over 120 years ago. The MO correlation was also observed with various biological effects and various chemicals, including alcohols; thus, the correlation represents a fundamental relationship between chemicals and organisms. The MO correlation was explained by the lipid and protein theories, although the debate has not been resolved and the principle remains unknown. MethodsThe gentle hydration method was used to form giant unilamellar vesicles (GUVs) consisting of high- and low-melting phospholipids and cholesterol in the presence of n-alcohols (C2-C12). Confocal fluorescence microscopy was used to determine the percentage of GUVs with domains in relation to the concentrations of n-alcohols. Resultsn-Alcohols inhibited the domain formation of GUVs, and the half inhibitory concentration (IC50) in the aqueous phase decreased exponentially with increasing chain length (lipophilicity). In contrast, the membrane concentrations of alcohols for the inhibition, which is a product of the membrane-water partition coefficient and the IC50 values, remained constant irrespective of the chain length. ConclusionsThe MO correlation is established in artificial lipid membrane, which supports the lipid theory. When alcohols reach the same critical concentration in the membrane, similar biological effects appear irrespective of the chain length, which is the principle underlying the MO correlation. Summary Statementn-Alcohols inhibit the domain formation of giant unilamellar vesicles according to the Meyer-Overton correlation.

biophysics↗

bioRxiv2020

Antimalarial drugs lose their activity with a slight drop in pH

Antimalarial drugs have antimicrobial, antiviral, antimalarial and immunosuppressive activities, although the mechanisms remain unknown. Quinacrine (QC) increases the antimicrobial activity against yeast exponentially with a pH-dependent increase in the cationic amphiphilic drug (CAD) structure. CAD-QC localizes in membranes and induces glucose starvation by noncompetitively inhibiting glucose uptake. A logarithmic increase in antimicrobial activity with pH-dependent CAD formation was also observed for chloroquine, indicating that the CAD structure is crucial for its pharmacological activity. A decrease in CAD structure with a slight decrease in pH from 7.4 greatly reduced their effects; namely, these drugs would inefficiently act on falciparum malaria and COVID-19 pneumonia patients with acidosis, resulting in resistance. Recovering normal blood pH or using pH-insensitive quinoline drugs might be effective.

pharmacology and toxicology↗