Rethinking Antioxidants in Lipid Dispersions and Cells through the Cut-off Effect
Mickaël Laguerre*, Jérôme Lecomte, Pierre Villeneuve 

It is generally admitted in food and drug research that antioxidant activity increases with lipophilicity, and that the most lipophilic compounds will have the highest activity. Using antioxidants grafted with various alkyl chains and assessed in systems containing lipid-water interfaces, we have demonstrated for the first time that this concept is imperfect, and that moderate to highly lipophilic antioxidants may display near-zero activities. In emulsified, membrane, and cell systems, the effectiveness of numerous homologous series of antioxidants increases as the alkyl chain is lengthened, with a threshold for a medium chain (typically 8-12 carbon atoms), beyond which further chain extension leads to a decrease in this activity. This presentation connects this non-linear phenomenon with the so-called “cut-off effect” documented since the 1930’s. This effect may also be related to Lipinsky’s rule of five. Putative mechanisms of action for the cut-off effect will be addressed in order to rationalize the sudden collapse of activity beyond a critical chain length. The pivotal question is to know whether the fact that this cut-off effect has been observed in oil-in-water emulsions, liposomes, and cells is just a coincidence, or more interestingly, if this phenomenon originated from the same mechanism of action.