Quercetin, Morin, Luteolin, and Phloretin Are Dietary Flavonoid Inhibitors of Monocarboxylate Transporter 6

Abstract

Monocarboxylate transporter 6 (MCT6; SLC16A5) has been recognized for its role as a xenobiotic transporter, with characterized substrates probenecid, bumetanide, and nateglinide. To date, the impact of commonly ingested dietary compounds on MCT6 function has not been investigated, and therefore, the objective of this study was to evaluate a variety of flavonoids for their potential MCT6-specific interactions. Flavonoids are a large group of polyphenolic phytochemicals found in commonly consumed plant-based products that have been recognized for their dietary health benefits. The uptake of bumetanide in human MCT6 gene-transfected Xenopus laevis oocytes was significantly decreased in the presence of a variety of flavonoids (e.g., quercetin, luteolin, phloretin, and morin), but was not significantly affected by flavonoid glycosides (e.g., naringin, rutin, phlorizin). The IC50 values of quercetin, phloretin, and morin were determined to be 25.3 ± 3.36, 17.3 ± 2.37, and 33.1 ± 3.29 μM, respectively. The mechanism of inhibition of phloretin was reversible and competitive, with a Ki value of 22.8 μM. Furthermore, typical MCT substrates were also investigated for their potential interactions with MCT6. Substrates of MCTs 1, 2, 4, 8, and 10 did not cause any significant decrease in MCT6-mediated bumetanide uptake, suggesting that MCT6 has distinct compound selectivity. In summary, these results suggest that dietary aglycon flavonoids may significantly alter the pharmacokinetics and pharmacodynamics of bumetanide and other MCT6-specific substrates, and may represent potential substrates for MCT6.

Intestinal disposition of quercetin and its phase-II metabolites after oral administration in healthy volunteers

“…In the intestinal lumen, quercetin and its excreted glucuronides can interact with uptake transporters. For example, quercetin has been shown to inhibit the monocarboxylate transporter 6 (MCT6) with an IC 50 of 25 μ m , which is in the same range of concentration found in this study. Flavonoid conjugates (including QGs) also inhibited organic anion transporters (OATs) transporters, which are also present in the intestine, although the isotypes investigated by Wong et al .…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…numbering). Expression of MCT6 in the human intestine was confirmed by Kohyama et al 8 Moreover, Jones et al 10 suggest high MCT6 expression in hepatocytes and intermediate levels in the kidneys and colon (abstracts.aaps.org, AAPS2016, 07M0330). Protein expression of human MCT9 was found in the proximal tubular epithelial cell of the kidneys.…”

“…For instance, for MCT6 transport of xenobiotics, such as loop diuretics (e.g., bumetanide), the antidiabetic drug nateglinide or the uricosuric agent probenecid was described 8, 9. In addition, in contrast to the typical MCT substrates, dietary flavonoids were recently proposed as substrate for MCT6, with additional inhibiting effect,10 suggesting distinct substrate specificities compared with MCT1–MCT4. The endogenous substrates of MCT6, however, are not identified so far.…”

Monocarboxylate Transporter 6-Mediated Interactions with Prostaglandin F2α: In Vitro and In Vivo Evidence Utilizing a Knockout Mouse Model

“…Briefly, cDNA was amplified using 5 and 3 primers prior to the restriction sites using reverse transcription polymerase chain reaction (RT-PCR) on a BioRad CFX Connect™ RT System. The PCR reaction was purified, and the cDNA and previously used oocyte expression vector (pGH19) [7,34] were double-digested with XmaI and XbaI. The digested PCR product and linearized vector were further purified and ligated using a T4 DNA ligase reaction mixture.…”

“…One of which, monocarboxylate transporter 6 (MCT6; SLC16A5), was found to be implicated in the transport of a wide variety of drugs (i.e., bumetanide, nateglinide, probenecid, and prostaglandin F 2α (PGF2α)), as well as dependent on pH and membrane potential [5,6]. In addition, our lab recently characterized MCT6 s interactions with a series of commonly ingested aglycone flavonoids, suggesting its role in their potential transport and/or drug-diet interactions [7]. Gene expression data suggest that MCT6 activity plays a primary role in tissues involved primarily in drug absorption and disposition, such as the kidney, liver, and intestine [6,8,9].…”