Curcumin Affects Phase II Disposition of Resveratrol Through Inhibiting Efflux Transporters MRP2 and BCRP
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.
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.
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.
These results suggest that curcumin alters the phase II distribution of resveratrol through inhibiting efflux transporters including MRP2 and BCRP.
KEY WORDSBCRP curcumin MRP2 phase II disposition resveratrol
Area under the plasma concentration curve
Breast cancer resistance protein
Hanks’ balanced salt solution
Multidrug resistance-associated protein
Tandem mass spectrometry
β-glucuronidases, sulfatase, 3′-Phosphoadenosine 5′-phosphosulfate
Uridine diphosphoglucuronic acid
Ultraperformance liquid chromatography
- 18.Polycarpou E, Meira LB, Carrington S, Tyrrell E, Modjtahedi H, Carew MA. Resveratrol 3-O-D-glucuronide and resveratrol 4′-O-D-glucuronide inhibit colon cancer cell growth: evidence for a role of A3 adenosine receptors, cyclin D1 depletion, and G1 cell cycle arrest. Mol Nutr Food Res. 2013;57:1708–17.PubMedGoogle Scholar
- 27.Mizuno N, Takahashi T, Kusuhara H, Schuetz JD, Niwa T, Sugiyama Y. Evaluation of the role of breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4) in the urinary excretion of sulfate and glucuronide metabolites of edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one). Drug Metab Dispos. 2007;35:2045–52.CrossRefPubMedGoogle Scholar
- 39.Jiang W, Xu B, Wu B, Yu R, Hu M. UDP-glucuronosyltransferase (UGT) 1A9-overexpressing HeLa cells is an appropriate tool to delineate the kinetic interplay between breast cancer resistance protein (BRCP) and UGT and to rapidly identify the glucuronide substrates of BCRP. Drug Metab Dispos. 2012;40:336–45.PubMedCentralCrossRefPubMedGoogle Scholar
- 53.Brand W, Oosterhuis B, Krajcsi P, Barron D, Dionisi F, van Bladeren PJ, et al. Interaction of hesperetin glucuronide conjugates with human BCRP, MRP2 and MRP3 as detected in membrane vesicles of overexpressing baculovirus-infected Sf9 cells. Biopharm Drug Dispos. 2011;32:530–5.CrossRefPubMedGoogle Scholar
- 56.Zamek-Gliszczynski MJ, Nezasa K, Tian X, Bridges AS, Lee K, Belinsky MG, et al. Evaluation of the role of multidrug resistance-associated protein (Mrp) 3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3−/− and Abcc4−/− mice. J Pharmacol Exp Ther. 2006;319:1485–91.CrossRefPubMedGoogle Scholar
- 57.Guo A, Marinaro W, Hu P, Sinko PJ. Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). Drug Metab Dispos. 2002;30:457–63.CrossRefPubMedGoogle Scholar