Intestinal breast cancer resistance protein (BCRP)/Bcrp1 and multidrug resistance protein 3 (MRP3)/Mrp3 are involved in the pharmacokinetics of resveratrol.
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(-/-) 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.
van de Wetering
Koen
K
Division of Molecular Biology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
Burkon
Alexander
A
Feddema
Wouter
W
Bot
Alice
A
de Jonge
Hugo
H
Somoza
Veronika
V
Borst
Piet
P
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D001693:Biological Transport, Active / Q000502:physiology; D002460:Cell Line; D020895:Enterocytes / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D000077185:Resveratrol; D018411:Spodoptera; D013267:Stilbenes / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000502:physiology; D022161:Transport Vesicles / Q000378:metabolism / Q000502:physiology
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D008565:Membrane Proteins; D013267:Stilbenes; C095122:multidrug resistance protein 3; D000077185:Resveratrol