Drug Metabolism and Pharmacokinetics 2014-01-01

Noncompetitive inhibition of proton-coupled folate transporter by myricetin.

Mai Furumiya, Katsuhisa Inoue, Chihiro Nishijima, Takahiro Yamashiro, Erina Inaoka, Kinya Ohta, Yayoi Hayashi, Hiroaki Yuasa

Index: Drug Metab. Pharmacokinet. 29(4) , 312-6, (2014)

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Abstract

Myricetin is a flavonoid that has recently been suggested to interfere with the intestinal folate transport system. The present study was conducted to examine that possibility, focusing on its inhibitory effect on proton-coupled folate transporter (PCFT) as the molecular entity of the transport system. The uptake transport of folate was first examined in the Caco-2 cell as an intestinal epithelial cell model, and its carrier-mediated component, of which the Michaelis constant (Km) was 0.407 µM, was found to be noncompetitively inhibited by myricetin with an inhibition constant (Ki) of 61 µM. Consistent with that, folate transport by human PCFT stably expressed in Madin-Darby canine kidney II (MDCKII) cells, of which the Km was 1.246 µM, was also noncompetitively inhibited by myricetin with a Ki of 130 µM. Thus, myricetin was suggested to inhibit intestinal folate transport by acting noncompetitively on PCFT, although the Km and Ki were similarly shifted to some extent to be smaller in Caco-2 cells. Finally, epigallocatechin-3-gallate was also suggested to act in a noncompetitive manner as an inhibitory flavonoid. Care may need to be taken, therefore, in the ingestion of myricetin and some flavonoids to maintain the absorption of folate and antifolate drugs.