Hydroxyl group abundance and lipid environment determine the cytotoxic activity of polyphenols

Polyphenols are plant secondary metabolites that contribute to defense against biotic and abiotic stressors. Their aromatic rings confer lipophilic properties, whereas hydroxyl groups determine their redox activity, suggesting that both structural features may influence their interaction with mitochondrial membranes and oxidative phosphorylation. However, the contribution of hydroxyl groups and a lipophilic environment to the biological activity of polyphenols remains poorly understood. This study investigated the effects of polyphenol structure and lipid environment on toxicity using Saccharomyces cerevisiae as a model organism. Four polyphenols with different numbers of hydroxyl groups and structural features (quercetin, naringenin, resveratrol, and gallic acid) were evaluated in the presence of different fatty acids to assess the influence of a lipophilic environment. The presence of fatty acids increased the observed cytotoxicity of polyphenols under our experimental conditions. Although these findings are consistent with enhanced activity in a lipophilic environment, our experimental design does not distinguish whether this effect results from increased interaction of polyphenols with cells, altered cellular susceptibility, or other mechanisms. Additionally, among the compounds tested, quercetin, which contains five hydroxyl groups, exhibited the highest toxicity, indicating a positive association between hydroxyl group abundance and biological activity. These findings indicate that both the lipid environment and the number of hydroxyl groups are important determinants of polyphenol toxicity. The enhanced activity of polyphenols in lipid as solvents provides new insights into their mechanism of action and may facilitate the development of technologies that exploit their biological properties.