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Organic anion transporting polypeptides and organic cation transporter 1 contribute to the cellular uptake of the flavonoid quercetin

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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.

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Acknowledgments

This work was funded by a grant of the Deutsche Forschungsgemeinschaft [DFG GL 588/3-1] and the “Johannes und Frieda Marohn-Stiftung an der Friedrich-Alexander-Universität Erlangen-Nürnberg.” We thank Prof. Jörg König (Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg) for providing the transporter expressing HEK293 cell lines (OATP1B1, OATP1B3, OATP2B1, OATP3A1, OATP4A1, OATP5A1, OCT1) and respective control cell lines.

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The authors declare that they have no conflict of interest.

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  1. Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054, Erlangen, Germany

    Hartmut Glaeser, Krystyna Bujok, Ingrid Schmidt, Martin F. Fromm & Kathrin Mandery

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  1. Hartmut Glaeser
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  2. Krystyna Bujok
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  3. Ingrid Schmidt
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  4. Martin F. Fromm
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Correspondence to Hartmut Glaeser.

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The present work was performed in fulfillment of the requirements for obtaining the degree “Dr. med.” for Hartmut Glaeser at the Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

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Glaeser, H., Bujok, K., Schmidt, I. et al. Organic anion transporting polypeptides and organic cation transporter 1 contribute to the cellular uptake of the flavonoid quercetin. Naunyn-Schmiedeberg's Arch Pharmacol 387, 883–891 (2014). https://doi.org/10.1007/s00210-014-1000-6

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