Structure characteristics for intestinal uptake of flavonoids in Caco-2 cells

Flavonoids are a large group of polyphenols and widely distributed in plant foods. Flavonoids exhibit various biological activities, such as anti-cancer, antioxidant and anti-inflammatory while poor oral bioavailability has been considered as a major hurdle in their use as functional foods. Cellular uptake and efflux of flavonoid implicates their bioavailability. To investigate the cellular uptake and efflux of flavonoids, 27 flavonoids were measured for their cellular uptake in Caco-2 cells with (CUV) and without (CU) the inhibitor of P-glycoprotein (P-gp) verapamil. Then, a quantitative structure-absorption relationship (QSAR) model containing 21 compounds as training set was obtained from their corresponding CU. The model showed good robustness and predictivity with a high cross-validation coefficient (Q(2)) value of 0.809 and Log of the octanol/water partition coefficient (SlogP) and atomic charge on carbon 5 (Q(C5)) were related to flavonoid uptake. The CUV of some flavonoids were significantly (p < 0.05 or p < 0.01) higher than their CU, suggesting that specific flavonoids are pumped out by P-gp. The structure-affinity relationship of flavonoids as substrates of P-gp was determined with the presence of 4'-OCH3, 3'-OCH3 and the absence of 3'-OH, 3-OH and 4'-OH favorable for the affinity of flavonoids. These results provide valuable information for screening flavonoids with good absorption and low affinity with transporters.