Evidence of Time-Dependent Hepatic Cytotoxicity and Mitochondrial Remodelling Induced by Palmitoyl Epigallocatechin Gallate vs. Its Native (Poly)Phenol.

Lipophenols, combining phenolic and lipid characteristics in an amphiphilic molecule, offer unique bioactive properties with therapeutic potential, including anti-inflammatory and anti-oxidant effects. Thus, palmitoyl-epigallocatechin gallate (PEGCG), a lipophilic derivative of the extensively studied (poly)phenol epigallocatechin gallate (EGCG), has been stressed concerning enhanced stability in lipid-rich environments and bioavailability due to improved cellular uptake. Nonetheless, the effect of lipophilic esterification on some cellular processes, particularly at the mitochondrial level, remains underexplored. According to this knowledge gap, the present study uncovered the cytotoxic and mitochondrial effects of PEGCG, in vitro, upon the liver hepatocarcinoma cell line HepG2. The range of determinations developed, including the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay, flow cytometry, and electron microscopy, allowed describing the distinct biological potential for both EGCG and PEGCG. Thus, while EGCG exhibited minimal cytotoxicity and apoptosis induction, PEGCG reduced cell viability dose-dependently at 24 h and triggered significant mitochondrial damage, including fragmentation and cristae loss, at 1 µmol/L. However, at 48 h, PEGCG-treated cells recovered viability and mitochondrial structure, suggesting the activation of adaptive mechanisms for the molecular changes induced by PEGCG. These findings underscore the dynamic interplay between lipophilic catechins and cellular stress responses, offering valuable insights into the PEGCG's potential as a therapeutic agent and laying a foundation for further exploration of its biological power.