RT Journal Article
SR Electronic
T1 MRP3 Is Responsible for the Efflux Transport of Curcumin Glucuronide from Hepatocytes to the Blood
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.089193
DO 10.1124/dmd.119.089193
A1 Yu-Meng Jia
A1 Ting Zhu
A1 Huan Zhou
A1 Jin-Zi Ji
A1 Ting Tai
A1 Hong-Guang Xie
YR 2020
UL http://dmd.aspetjournals.org/content/early/2020/01/03/dmd.119.089193.abstract
AB Curcumin, a major polyphenol present in turmeric, is predominantly converted to curcumin-O-glucuronide (COG) in enterocytes and hepatocytes via glucuronidation. COG is a principal metabolite of curcumin in plasma and faeces. It appears that the efflux transport of the glucuronide conjugates of many compounds is mediated largely by MRP3 (multidrug resistance-associated protein 3, the gene product of the Abcc3). However, it is currently unknown whether this was the case with COG. In this study, Mrp3 knock-out (KO) and wild-type (WT) mice were used to evaluate the pharmacokinetics profiles of COG, the liver-to-plasma ratio of COG, and the COG-to-curcumin ratio in plasma, respectively. The ATP-dependent uptake of COG into recombinant human MRP3 inside-out membrane vesicles was measured for further identification, with estradiol-17β-D-glucuronide used in parallel as the positive control. Results showed that plasma COG concentrations were extremely low in KO mice compared to WT mice, that the liver-to-plasma ratios of COG were 8-fold greater in KO mice than in WT mice, and that the ATP-dependent uptake of COG at 1 or 10 μM was 5.0- and 3.1-fold greater in the presence of ATP than in the presence of AMP, respectively. We conclude that Mrp3 is identified to be the main efflux transporter responsible for the transport of COG from hepatocytes into the blood.SIGNIFICANCE STATEMENT This study was designed to elucidate the involvement of Mrp3 (multidrug resistance-associated protein 3) in the efflux transport of curcumin-O-glucuronide from hepatocytes into the blood using Mrp3 knock-out mice and to further corroborate mouse-derived findings using recombinant human MRP3 inside-out membrane vesicles. In this study, we identified that curcumin-O-glucuronide, a major metabolite of curcumin present in plasma and faeces, is a typical substrate of Mrp3 in mice and in humans. These new observations suggest that herb-drug interactions would occur in patients who concomitantly receive curcumin and either an MRP3 substrate/inhibitor or a drug that is glucuronidated by UGTs dominantly. In view of the widespread use of curcumin globally, such herb-drug interactions are of clinical importance.