Glaeser Hartmut, Bujok Krystyna, Schmidt Ingrid, Fromm Martin F, Mandery Kathrin
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054, Erlangen, Germany,
Naunyn Schmiedebergs Arch Pharmacol. 2014 Sep;387(9):883-91. doi: 10.1007/s00210-014-1000-6. Epub 2014 Jun 20.
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.
槲皮素和山奈酚等黄酮类化合物具有多种健康保护作用，如抗癌作用。它们是有机阴离子转运多肽（OATP）和有机阳离子转运体（如OCT2）的抑制剂。然而，对于这些转运体是否有助于黄酮类化合物的细胞摄取，人们了解甚少。因此，我们使用稳定表达不同人类OATP或OCT1的HEK293细胞系，研究了山奈酚和槲皮素的细胞摄取情况。山奈酚不是任何所研究转运体（OATP1A2、OATP1B1、OATP1B3、OATP2A1、OATP2B1、OATP3A1、OATP4A1、OATP5A1和OCT1）的底物。与对照细胞相比，槲皮素在HEK293 - OATP1A2、HEK293 - OATP2A1、HEK293 - OATP2B1和HEK293 - OCT1细胞中的摄取量显著更高。已知抑制剂柚皮苷、环孢素A和奎尼丁分别抑制了OATP1A2、OATP2B1和OCT1介导的槲皮素摄取。前列腺素E2和双氯芬酸未抑制槲皮素在HEK29３ - OATP2A1细胞中的细胞积累。离子载体羰基氰化物4 - （三氟甲氧基）苯腙（FCCP）通过增加HEK293对照细胞中的摄取量并使HEK293 - OATP2B1细胞无显著变化，从而降低了槲皮素的净摄取量，这表明槲皮素跟随FCCP驱动的质子流穿过质膜。除了被动扩散外，溶质载体转运体OATP1A2、OATP2B1和OCT1也有助于槲皮素的细胞积累。
