Escaping from the Cutoff Paradox by Accumulating Long-Chain Alcohols in the Cell Membrane

The mechanism for the cutoff, an activity cliff at which long-chain alcohols lose their biological effects, has not been elucidated. Highly hydrophobic oleyl alcohol (C_18:1) exists as a mixture of monomers and aggregated droplets in water. C_18:1 did not inhibit the yeast growth but inhibited the growth of the slime mold without a cell wall. C_18:1 exhibited toxicity to the yeast protoplast, which was enhanced by polyethylene glycol, a fusogen. Therefore, direct interactions of C_18:1 with the membrane are crucial for the toxicity. The cutoff alcohols, C₁₄ and C₁₆, also exhibited strong toxicity obeying the Meyer-Overton correlation, in intact yeast cells whose membrane growth was suppressed in water. Taken together, the cutoff is avoidable by securing sufficient accumulation of the wall-permeable monomers in the membrane, which supports the lipid theory. It would be important to distinguish the effective drug structure localizing in the membrane and deal with the amount in the membrane.