Threshold protective effect of deuterated polyunsaturated fatty acids on peroxidation of lipid bilayers

Abstract

Autoxidation of polyunsaturated fatty acids (PUFAs) damages lipid membranes and generates numerous toxic by‐products implicated in neurodegeneration, aging and other pathologies. Abstraction of bis‐allylic hydrogen atoms is the rate‐limiting step of PUFA autoxidation, which is inhibited by replacing bis‐allylic hydrogens with deuterium atoms (D‐PUFAs). In cells, the presence of a relatively small fraction of D‐PUFAs among natural PUFAs is sufficient to effectively inhibit lipid peroxidation. Here, we investigate the effect of various D‐PUFAs on the stability of liposomes under oxidative stress conditions. The permeability of vesicle membranes to fluorescent dyes was measured as a proxy for bilayer integrity, and the formation of conjugated dienes was monitored as a proxy for lipid peroxidation. Remarkably, both approaches reveal a similar threshold for the protective effect of D‐PUFAs in liposomes. We show that protection rendered by D‐PUFAs depends on the structure of the deuterated fatty acid. Our findings suggest that protection of PUFAs against autoxidation depends on the total level of deuterated bisallylic (CD₂) groups present in the lipid bilayer. However, the phospholipid containing 6,6,9,9,12,12,15,15,18,18‐d₁₀‐docosahexaenoic acid (D10‐DHA) exerts a stronger protective effect than should be expected from its deuteration level. These findings further support the application of D‐PUFAs as preventive/therapeutic agents in numerous pathologies that involve lipid peroxidation.