Curcumin Affects Phase II Disposition of Resveratrol Through Inhibiting Efflux Transporters MRP2 and BCRP.
OBJECTIVE
To evaluate the impact of curcumin on the disposition of resveratrol phase II metabolites in vivo, and explain the observations by performing in vitro studies in transporter-overexpressed cells.


METHODS
Pharmacokinetic studies of resveratrol with and without the co-administration of curcumin were performed in both FVB wild-type and Bcrp1 (-/-) mice. Human UGT1A9-overexpressing HeLa cells and human MRP2-overexpressing MDCK II-UGT1A1 cells were used as in vitro tools to further determine the impact of curcumin as a transporter inhibitor on resveratrol metabolites.


RESULTS
We observed higher exposure of resveratrol conjugates in Bcrp1 (-/-) mice compared to wild-type mice. In wild-type mice, curcumin increased the AUC of resveratrol glucuronide by 4-fold compared to the mice treated without curcumin. The plasma levels of resveratrol and its sulfate conjugate also increased moderately. In Bcrp1 (-/-) mice, there was a further increase (6-fold increase) in AUC of resveratrol glucuronide observed when curcumin was co-administered compared to AUC values obtained in wild-type mice without curcumin treatment. In the presence of 50 nM curcumin, the clearance of resveratrol-3-O-glucuronide and resveratrol-3-O-sulfate reduced in both MRP2-overexpressing MDCKII-UGT1A1 cells and Human UGT1A9-overexpressing HeLa cells.


CONCLUSIONS
These results suggest that curcumin alters the phase II distribution of resveratrol through inhibiting efflux transporters including MRP2 and BCRP.
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston, 1441 Moursund Street, Houston, Texas, 77030, USA.
Shufan
S
Ge
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston, 1441 Moursund Street, Houston, Texas, 77030, USA.
Taijun
T
Yin
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston, 1441 Moursund Street, Houston, Texas, 77030, USA.
Beibei
B
Xu
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston, 1441 Moursund Street, Houston, Texas, 77030, USA.
Song
S
Gao
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston, 1441 Moursund Street, Houston, Texas, 77030, USA. mhu@uh.edu.
Ming
M
Hu
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D003474:Curcumin / Q000494:pharmacology*; D004285:Dogs; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D026901:Membrane Transport Proteins; D050217:Metabolic Detoxication, Phase II / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism*; D000090264:UDP-Glucuronosyltransferase 1A9
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D003474:Curcumin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D000077185:Resveratrol; D013267:Stilbenes; D000090264:UDP-Glucuronosyltransferase 1A9; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C000715591:UGT1A9 protein, human; C000715592:Ugt1a9 protein, mouse; C499731:resveratrol-4'-O-glucuronide
BCRP; MRP2; curcumin; phase II disposition; resveratrol