Different effects of l- and d-menthol on the microstructure of ceramide 5/cholesterol/palmitic acid bilayers

The optical activity of transdermal permeation enhancers is one of the crucial factors for the enhancement of drug permeation via the skin. We investigated the effects of optically active menthols on a lipid bilayer model composed of ceramide 5, cholesterol, and palmitic acid. We first examined the fluidizing effects of l- and d-menthols on the lipid bilayers. The fluorescence anisotropy and thermodynamic parameters, such as the transition temperature and transition enthalpy, were significantly reduced by treatment with the optically active menthols. The effects of d-menthol were stronger than those of l-menthol. To discuss further, we also performed a detergent insolubility study and measured wide angle X-ray scattering. The amount of liquid-ordered phase membranes in the bilayers was significantly reduced by treatment with d-menthol. Whereas, l-menthol did not affected to the liquid-ordered phase membranes. The apparent ratio of orthorhombic hydrocarbon chain packing was substantially reduced by treatment with l-menthol. Thus, the distinct effects of optically active menthols on lipid bilayers were clarified: l-menthol acts on orthorhombic hydrocarbon chain packing with high selectivity, whereas d-menthol has no such specific effect. These findings extend our understanding of the mechanisms by which menthols affect the intercellular lipids in the stratum corneum.