Intestinal Breast Cancer Resistance Protein (BCRP)/Bcrp1 and Multidrug Resistance Protein 3 (MRP3)/Mrp3 Are Involved in the Pharmacokinetics of Resveratrol

Abstract

The phytoestrogen resveratrol has putative health-promoting effects and is present in several dietary constituents. Resveratrol is metabolized extensively in the gut epithelium, resulting in the formation of hydrophilic glucuronic acid and sulfate conjugates. These polar resveratrol conjugates need specific transporters to cross the cell membrane. We show here that vectorial transport of some of these metabolites is mediated by multidrug resistance protein 3 (MRP3, ABCC3) and/or breast cancer resistance protein (BCRP, ABCG2) located in the basolateral and apical membranes of enterocytes, respectively. In vitro, MRP3 transports resveratrol-glucuronide (Res-3-G). The absence of Mrp3 in mice results in altered disposition of Res-3-G and its parent compound resveratrol, leading to a reduced percentage of resveratrol being excreted via the urine in Mrp3(Ϫ/Ϫ) mice. Circumstantial evidence suggests that circulating resveratrol is formed by deglucuronidating Res-3-G in vivo, providing a possible explanation for the health beneficial effects of resveratrol in vivo, despite its rapid and extensive conjugation. BCRP transports Res-3-G and resveratrol sulfates in vitro, and its absence in mice results in high plasma levels of resveratrol-di-sulfate, a resveratrol metabolite hardly detectable in the plasma of wild-type mice and in an increased disposal of resveratrol via the urine. The profound effects of ATP-binding cassette transporters on the disposal of resveratrol may be representative for the handling of several other polyphenols of dietary origin.

Improving the oral bioavailability of beneficial polyphenols through designed synergies

“…Transgenic mice deficient in BCRP exhibit greatly increased plasma bioavailability of resveratrol and its metabolites mediated by an enhanced absorption through gut epithelia [80]. Interestingly, not all of the ABC transporters efflux xenobiotics back into the gut lumen after oral consumption (see [6] for review and Fig.…”

“…For example, the MRP3 transporter pumps xenobiotics into the basolateral side (or blood side) of gut epithelia. Resveratrol is a substrate for this pump, and MRP3-deficient mice have been shown to have significantly decreased plasma levels of resveratrol and its metabolites following the oral consumption [80].…”

Lack of ABCG2 Shortens Latency of BRCA1-Deficient Mammary Tumors and This Is Not Affected by Genistein or Resveratrol

“…We have previously shown that lack of ABCG2 results in increased plasma levels of resveratrol and its metabolites in FVB/N mice (22). Hence, any antagonizing effects of this phytoestrogen on mammary tumor development should even be more pronounced in these ABCG2-deficient K14cre;Brca1 F/F ;p53 (Fig.…”

Anticancer Activities of Resveratrol in Colorectal Cancer

“…Residual intracellular resveratrol glucuronide is released through the serosa into the bloodstream by another multidrug resistanceassociated protein 3 (MRP3). MRP3 is an ABC-transporter that transports resveratrol and other polyphenolic compounds as well riboflavin and biotin into the bloodstream [31]. Once in the blood, resveratrol can be transported as the glucuronide bound to albumin [26,32].…”