Inhibition of P-glycoprotein in Caco-2 cells: Effects of herbal remedies frequently used by cancer patients

Abstract

1. The herbal products Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic were investigated for in vitro inhibitory potential on P-glycoprotein (P-gp)-mediated transport of digoxin (30 nM) in differentiated and polarized Caco-2 cells. 2. Satisfactory cell functionality was demonstrated through measurements of assay linearity, transepithelial electric resistance (TEER), cytotoxicity, mannitol permeability, and inclusion of the positive inhibition control verapamil. 3. The most potent inhibitors of the net digoxin flux (IC₅₀) were mistletoe > Natto K2 > Agaricus > green tea (0.022, 0.62, 3.81, >4.5 mg ml⁻¹, respectively). Mistletoe also showed the lowest IC₂₅ value, close to that obtained by verapamil (1.0 and 0.5 µg ml⁻¹, respectively). The IC₅₀/IC₂₅ ratio was found to be a good parameter for the determination of inhibition profiles. Garlic and noni juice were classified as non-inhibitors. 4. This study shows that mistletoe, Natto K2, Agaricus and green tea inhibit P-gp in vitro. Special attention should be paid to mistletoe due to very low IC₅₀ and IC₂₅ values and to Natto K2 due to a low IC₅₀ value and a low IC₅₀/IC₂₅ ratio.

Keywords:

• Herb–drug interactions
• in vitro
• digoxin
• efflux transporter
• P-glycoprotein inhibitors
• Natto K2
• Agaricus
• mistletoe
• noni juice
• green tea
• garlic
• Caco-2 cell transport
• digoxin cellular transport

Acknowledgements

The authors thank Dorine Ateba and Anne Lise Ustad for technical assistance in this study, and also Bent Hellum, Ane Djuv and Torstein S. Hansen for valuable discussions and support. This study was supported by the Norwegian Cancer Society and Eckbos Legacies.