Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, and ‡Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York , Buffalo, New York 14214, United States.
Mol Pharm. 2017 Sep 5;14(9):2930-2936. doi: 10.1021/acs.molpharmaceut.7b00264. Epub 2017 May 31.
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 IC 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 K 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.
单羧酸转运蛋白 6（MCT6；SLC16A5）作为一种异生物质转运蛋白的作用已得到认可，其特征底物有丙磺舒、布美他尼和那格列奈。迄今为止，尚未研究通常摄入的饮食化合物对 MCT6 功能的影响，因此，本研究的目的是评估各种类黄酮对 MCT6 特异性相互作用的潜在影响。类黄酮是一大类多酚植物化学物质，存在于人们经常食用的植物性产品中，因其对饮食健康的益处而受到认可。在存在各种类黄酮（如槲皮素、木樨草素、根皮苷和桑色素）的情况下，人 MCT6 基因转染非洲爪蟾卵母细胞摄取布美他尼的能力显著降低，但类黄酮糖苷（如柚皮苷、芦丁、根皮苷）对其没有显著影响。槲皮素、根皮苷和桑色素的 IC值分别确定为 25.3±3.36、17.3±2.37 和 33.1±3.29μM。根皮苷抑制作用的机制是可逆和竞争性的，K 值为 22.8μM。此外，还研究了典型的 MCT 底物与 MCT6 之间的潜在相互作用。MCT1、2、4、8 和 10 的底物未导致 MCT6 介导的布美他尼摄取明显减少，这表明 MCT6 具有独特的化合物选择性。综上所述，这些结果表明，饮食非糖苷类黄酮可能会显著改变布美他尼和其他 MCT6 特异性底物的药代动力学和药效学，并且可能是 MCT6 的潜在底物。
