Effects of citrus fruit juices on cytotoxicity and drug transport pathways of Caco-2 cell monolayers

The aim of this study was to correlate the taxonomy of grapefruit, pummelo, orange, lime and lemon with fruit juice-mediated cytotoxicity, modulation of epithelial permeability and P-glycoprotein (P-gp)-mediated efflux using 0–50% juice concentrations. Lime and lemon juices at 30% enhanced the absorption of [14C]-mannitol across Caco-2 cell monolayers by six- and eight-fold, respectively, but grapefruit and pummelo juices did not modulate the paracellular [14C]-mannitol transport even at 50%. Orange juice at 30% increased mannitol absorption to a comparable level as lime juice, but had minimal effects on TEER. All five juices did not modulate the passive diffusional pathway as exemplified by their negligible effects on [3H]-propranolol absorption. Grapefruit, pummelo and orange juices showed P-gp inhibitory activity by reducing rhodamine-123 (R-123) efflux and elevating R-123 cellular accumulation, but lime and lemon juices did not. Lime and lemon juices at ≥30% were cytotoxic towards Caco-2 cells. Grapefruit and pummelo juices at 10% did not affect Caco-2 cell viability, but they enhanced cell growth at concentrations of ≥30%. Orange juice increased cell viability only at lower concentrations. On the basis of these data, lime and lemon juices could be regarded as a group distinct from grapefruit and pummelo juices, while orange juice appeared to belong to a bridging group. This grouping was consistent with the categorization of the citrus fruits according to their dominant flavonoid pattern and taxonomy.