Interaction characteristics of flavonoids with human organic anion transporter 1 (hOAT1) and 3 (hOAT3)

Abstract

The present study aimed to investigate the interaction characteristics of flavonoids with human organic anion transporter 1 (hOAT1) and 3 (hOAT3). Five flavonoids (morin, silybin, naringin, naringenin and quercetin) were selected and their interaction characteristics with hOAT1 and hOAT3 were examined in MDCK cells overexpressing hOAT1 or hOAT3. Among tested flavonoids, morin and silybin exhibited significant inhibition effects on the cellular uptake of [³H]-para-aminohippuric acid ([³H]-PAH) in MDCK–hOAT1 cells with K_i of 0.46 μM and 24 μM, respectively, while all the tested flavonoids appeared to be less interactive with hOAT3 compared to hOAT1. A kinetic study suggested that morin and silybin inhibited hOAT1-mediated cellular uptake of [³H]-PAH in a competitive manner. Furthermore, morin and silybin were translocated by hOAT1 across the cellular membrane. In conclusion, the present study identified some of flavonoids as a new class of hOAT1 inhibitors, suggesting a potential for flavonoid–drug interactions via the modulation of hOAT1 activity.

Introduction

As public interest in complementary and alternative medicines increases substantially, various herbal products are available over the counter in the form of phytopharmaceuticals and the use of herbal products has become more popular for health maintenance or as an adjunct to the mainstream medical care [1], [2]. Accordingly, there is increasing risk of herbal ingredient-mediated pharmacokinetic interactions with conventional medications as indicated by numerous studies elsewhere [3], [4], [5]. Among plant polyphenolic compounds, flavonoids are widely present in fruits, vegetables, plant-derived foods and beverages and have shown various biological activities including anticancer and anti-oxidation [6], [7], [8], [9]. Furthermore, flavonoids are known to affect drug absorption and disposition via the modulation of drug metabolizing enzymes as well as drug transporters [10], [11]. So far, numerous studies have been done for the interaction of flavonoids with ATP-binding cassette (ABC) efflux transporters such as P-gp, MRP1, MRP2 and ABCG2 [11], [12] but only few studies have been conducted to elucidate the interaction of flavonoids with uptake transporters. For example, several studies have demonstrated that some of herbal extracts as well as citrus juices could inhibit the OATP-B-mediated cellular uptake of certain drugs during the intestinal absorption [13], [14], [15]. Also, Wang et al. [16], [17] have reported that flavonoids could modulate the activity of other uptake transporters such as MCT1 and OATP1B1 (OATP-C). However, little is yet known about the potential interaction of flavonoids with uptake transporters expressed in the kidney.

Organic anion transporters (OATs) located in the apical and basolateral membranes of tubular epithelial cells play a critical role in the distribution and elimination of structurally diverse organic anions including various therapeutics [18], [19]. Among OATs, hOAT1 and hOAT3 are localized in the basolateral membrane of the proximal tubular cells and their expression levels appeared to be much higher than those of other organic anion transporters in the human kidney cortex [20]. Furthermore, many previous studies have reported that hOAT1 and hOAT3 actively involved in the tubular uptake of various therapeutics [18], [19]. Therefore, the modulators of hOAT1 and hOAT3 activities may have high potential for drug interactions in the combination therapy and alter the pharmacokinetics of various xenobiotics particularly that are eliminated from the body mainly via urinary excretion. Indeed, the competition for those transporters could cause the retention of certain drugs including acyclovir, zidovudine and penicillin, resulting in longer plasma half-lives of drugs [21], [22], [23].

Given that the activities of hOAT1 and hOAT3 are important determinants for the pharmacokinetics of various drugs, elucidation of the interaction characteristics of flavonoids with those drug transporters will help us to predict potential flavonoid–drug interactions via the modulation of renal excretion and may lead us to the certain therapeutic benefit in current medical practice. Therefore, the present study aimed to investigate the modulation of hOAT1 and hOAT3 activities by naturally occurring flavonoids. Five flavonoids with structural variation (Fig. 1) were selected and their interaction characteristics with hOAT1 and hOAT3 were examined by using MDCK cells overexpressing hOAT1 or hOAT3.