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

Int J Pharm. 2006 Jan 3;307(1):42-50. doi: 10.1016/j.ijpharm.2005.09.017. Epub 2005 Nov 2.


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 >or=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 >or=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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption
  • Beverages* / toxicity
  • Biological Transport / drug effects
  • Caco-2 Cells
  • Carbon Radioisotopes
  • Cell Membrane Permeability / drug effects
  • Cell Survival / drug effects
  • Citrus* / classification
  • Food-Drug Interactions*
  • Humans
  • Mannitol / metabolism
  • Propranolol / metabolism


  • Carbon Radioisotopes
  • Mannitol
  • Propranolol