Inhibitory Effect of Caffeic Acid on Human Organic Anion Transporters hOAT1 and hOAT3: A Novel Candidate for Food–Drug Interaction

Abstract

Several kinds of food have been shown to influence the absorption and metabolism of drugs, although there is little information about their effect on the renal excretion of drugs. In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effects of chlorogenic acid, caffeic acid and quinic acid, which are contained in coffee, fruits and vegetables, on human organic anion transporters hOAT1 and hOAT3; these transporters mediate renal tubular uptake of anionic drugs from blood. Injection of hOAT1 and hOAT3 cRNA into oocytes stimulated uptake of typical substrates of hOAT1 and hOAT3 (p-aminohippurate and estrone sulfate, respectively); among the three compounds tested, caffeic acid most strongly inhibited these transporters. The apparent 50% inhibitory concentrations of caffeic acid were estimated to be 16.6 µM for hOAT1 and 5.4 µM for hOAT3. Eadie-Hofstee plot analysis showed that caffeic acid inhibited both transporters in a competitive manner. In addition to the transport of p-aminohippurate and estrone sulfate, that of antifolates and antivirals was inhibited by caffeic acid. These findings show that caffeic acid has inhibitory potential against hOAT1 and hOAT3, suggesting that renal excretion of their substrates could be affected in patients consuming a diet including caffeic acid.

Transport of Xanthurenic Acid by Rat/Human Organic Anion Transporters OAT1 and OAT3

“…Previously, our laboratory showed that the IC 50 values of caffeic acid were 16.6 mM for hOAT1 and 5.4 mM for hOAT3, and that the influence of chlorogenic acid and quinic acid was much weaker than that of caffeic acid. 15) The IC 50 values and K i values of most nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to be lower than 20 mM, but the K i values of salicylate were exceptionally high, 407 mM for hOAT1 and 111 mM for hOAT3. 16,17) Salicylate, chlorogenic acid, and quinic acid have a typical anionic moiety carboxyl group that binds directly to the benzene ring or the six-membered ring, although there is a methylene group, methine group, or vinylene group between the rings and the carboxyl group in caffeic acid and almost NSAIDs.…”

Caffeic acid inhibits organic anion transporters OAT1 and OAT3 in rat kidney

“…Previously, we estimated the apparent 50% inhibitory concentrations of caffeic acid for hOAT1 and hOAT3 to be 16.6 and 5.4 µM, respectively [10]. As represented in Figure 1, caffeic acid at 10 µM reduced the transport activity of p-aminohippurate by hOAT1 to 50%, and the transport activity of estrone sulfate by hOAT3 to 72% (Figure 1).…”

“…On OAT1 and OAT3, some food ingredients including ellagic acid and flavonoids were exhibited to interact with the transporters [8,9]. Furthermore, we identified caffeic acid as the potent inhibitor for human OAT1 (hOAT1) and hOAT3 [10]. Subsequently, Wang and Sweet examined the inhibitory effects of other dietary phenolic acids on hOATs and showed the great inhibitory potencies of ferulic acid, gallic acid, and sinapinic acid for hOAT1 and hOAT3 [11].…”

“…pBK-CMV plasmid vectors containing cDNA of rOAT1 or rOAT3 were a kind gift from Prof. Ken-ichi Inui (Kyoto University Hospital, Kyoto, Japan). The uptake experiment using Xenopus laevis oocytes was performed as previously reported [10]. Briefly, capped RNA encoding each OAT was transcribed from the appropriate restriction enzymelinearized pBK-CMV containing cDNA of rOAT1 or rOAT3 with T3 RNA polymerase.…”

Flavonoids Are Inhibitors of Human Organic Anion Transporter 1 (OAT1)–Mediated Transport

“…Recently, several dietary phenolic acids, including ellagic acid, caffeic acid, ferulic acid, gallic acid, sinapinic acid, and vanillic acid, have been reported to have a potent inhibitory effect on OATs, including OAT1 (Whitley et al, 2005;Uwai et al, 2011;Wang and Sweet, 2012b). In addition, the active components of a few medicinal herbs, including Salvia miltiorrhiza (Danshen) and Rheum sp., have also been found to potently interfere with OAT-mediated renal elimination (Wang and Sweet, 2012a;Wang et al, 2013).…”