title: Organic anion transporting polypeptides and organic cation transporter 1 contribute to the cellular uptake of the flavonoid quercetin.
abstract: Flavonoids such as quercetin and kaempferol mediate several health protective effects, e.g., anticancer effects. They are inhibitors of organic anion transporting polypeptides (OATP) and organic cation transporters (e.g., OCT2). However, little is known whether such transporters contribute to the cellular uptake of flavonoids. Therefore, we investigated the cellular uptake of kaempferol and quercetin using HEK293 cell lines stably expressing different human OATPs or OCT1. Kaempferol was not a substrate of any of the investigated transporters (OATP1A2, OATP1B1, OATP1B3, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OATP5A1, and OCT1). Quercetin showed a significantly higher uptake into the HEK293-OATP1A2, HEK293-OATP2A1, HEK293-OATP2B1, and HEK293-OCT1 cells compared to control cells. The OATP1A2-, OATP2B1-, and OCT1-mediated quercetin uptake was inhibited by known inhibitors such as naringin, cyclosporin A, and quinidine, respectively. The cellular accumulation of quercetin into HEK293-OATP2A1 cells was not inhibited by prostaglandin E2 and diclofenac. The ionophore carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) reduced the net uptake of quercetin by increasing the uptake in the HEK293-control cells and causing no significant change in the HEK293-OATP2B1 cells indicating that quercetin follows the FCCP-driven proton flux through the plasma membrane. In addition to passive diffusion, the SLC transporters OATP1A2, OATP2B1, and OCT1 contribute to cellular accumulation of quercetin.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054, Erlangen, Germany, hartmut.glaeser@pharmakologie.med.uni-erlangen.de.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Glaeser
authors.forename: Krystyna
authors.initials: K
authors.lastname: Bujok
authors.forename: Ingrid
authors.initials: I
authors.lastname: Schmidt
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mandery
mesh_terms: D001692:Biological Transport; D057809:HEK293 Cells; D006801:Humans; D044949:Kaempferols / Q000494:pharmacology; D027361:Organic Anion Transporters / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*
chemical_list: D044949:Kaempferols; D027361:Organic Anion Transporters; D027702:Organic Cation Transporter 1; C006552:kaempferol; D011794:Quercetin