Published online Dec 9, 2013. doi: 10.5497/wjp.v2.i4.115
Revised: September 17, 2013
Accepted: October 18, 2013
Published online: December 9, 2013
Processing time: 173 Days and 2.7 Hours
AIM: To evaluate the inhibitory effects of apigenin and kaempferol on the uptake of several important solute carrier (SLC) transporters.
METHODS: Various SLC transporters including the essential human organic anion transporter 1 (OAT1), OAT2, OAT3 and OAT4 as well as the important organic cation transporter 1 (OCTN1) and OCTN2, were over-expressed in human embryonic kidney (HEK)-293 cells, a well-established cell model of transporter studies. Transport uptake assay was performed 24 h after the transfection. The transport activity was assessed with the uptake of previously determined transporter model substrates and the inhibitory effect of apigenin and kaempferol was evaluated with the substrate uptake in the presence of 10 μmol/L of each compound. Uptake measurements with varying concentrations of inhibitors (ranged from 0.0001 to 50 μmol/L) were performed to further characterize the inhibitory potency of apigenin and kaempferol. The IC50 value (the concentration that inhibits 50% of the transporter function) of each compound was then calculated by the nonlinear regression model of Graphpad Prism 6.0 software.
RESULTS: Our data indicated that apigenin could potently inhibit the uptake of estrone-3-sulfate (ES) mediated by the HEK-293 cells expressing OAT2, OAT3 and OAT4 as well as the L-ergothioneine uptake via OCTN1-expressing HEK-293 cells. Among these transporters, the most prominent inhibition of apigenin was observed in the case of OAT3. Kaempferol showed significant inhibitory effects on the uptake of ES mediated through OAT2 and OAT3. Impaired L-ergothioneine uptake due to the presence of kaempferol was also observed in OCTN1-expressing HEK-293 cells. Similar to apigenin, kaempferol showed the most potent inhibitory effect on OAT3 as well. To further assess the inhibitory potencies of these two compounds on the uptake of ES mediated by OAT3-expressing HEK-293 cells, their IC50 values were then determined. Both chemicals showed pronounced inhibitory potencies on OAT3 with the IC50 values of 1.7 ± 0.1 and 1.0 ± 0.1 μmol/L (P < 0.01) for apigenin and kaempferol, respectively.
CONCLUSION: Both apigenin and kaempferol are potent inhibitors of OAT3; precautions will be necessary when co-administrating them with drugs that are substrates of OAT3.
Core tip: Our study showed that both apigenin and kaempferol could significantly inhibit various solute carrier transporters, in particular organic anion transporter 3, at their clinical doses. Inhibition on these transporters can greatly impact on pharmacokinetic performance of drugs that are substrates of these transporters by altering their absorption, distribution and excretion. Precautions should be implemented when co-administering apigenin and kaempferol with drugs that are substrates of these specific solute carrier transporters, in order to maximise desired therapeutic outcomes and avoid unexpected toxicities. This overall enhances our understanding of drug-drug/herb interactions related to apigenin and kaempferol and provides critical information to improve future multi-drug therapies.