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

Abstract

Organic anion transporter 1 (OAT1) has been reported to be involved in the nephrotoxicity of many anionic xenobiotics. As current clinically used OAT1 inhibitors are often associated with safety issues, identifying potent OAT1 inhibitors with little toxicity is of great value in reducing OAT1-mediated drug nephrotoxicity. Flavonoids are a class of polyphenolic compounds with exceptional safety records. Our objective was to evaluate the effects of 18 naturally occurring flavonoids, and some of their glycosides, on the uptake of para-aminohippuric acid (PAH) in both OAT1-expressing and OAT1-negative LLC-PK1 cells. Most flavonoid aglycones produced substantial decreases in PAH uptake in OAT1-expressing cells. Among the flavonoids screened, fisetin, luteolin, morin, and quercetin exhibited the strongest effect and produced complete inhibition of OAT1-mediated PAH uptake at a concentration of 50 mM. Further concentration-dependent studies revealed that both morin and luteolin are potent OAT1 inhibitors, with IC 50 values of <0.3 and 0.47 mM, respectively. In contrast to the tested flavonoid aglycones, all flavonoid glycosides had negligible or small effects on OAT1. In addition, the role of OAT1 in the uptake of fisetin, luteolin, morin, and quercetin was investigated and fisetin was found to be a substrate of OAT1. Taken together, our results indicate that flavonoids are a novel class of OAT1 modulators. Considering the high consumption of flavonoids in the diet and in herbal products, OAT1-mediated flavonoid-drug interactions may be clinically relevant. Further investigation is warranted to evaluate the nephroprotective role of flavonoids in relation to drug-induced nephrotoxicity mediated by the OAT1 pathway.

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

“…13,16,22,23 Lastly, the mechanism of inhibition was investigated for a potent flavonoid inhibitor of MCT6, phloretin.…”

“…14,15 Flavonoids have been demonstrated to be substrates and potent inhibitors of many members of the organic anion transporter family, including MCTs, 16,17 and cause significant drug–food interactions. 18–21 More specifically, flavonoids have been reported to interact with organic anion transporters MCT1, 16 OAT1, 22 and OATP1B1. 23 Flavonoids are eliminated predominantly by metabolism, resulting in high plasma concentrations of flavonoid metabolites.…”

Flavonoids as modulators of metabolic enzymes and drug transporters

“…Among the ten human OAT transporters, OAT1 and OAT3 are highly expressed on the basolateral membranes of proximal renal tubules, where they mediate the tubular uptake of a wide range of small and hydrophilic organic anions, some of them (β‐lactam antibiotics, antiviral agents, mercury, ochratoxin) responsible for renal injury. Therefore, OAT1 and/or OAT3 inhibition seems to be an important approach in the management of drug‐induced nephrotoxicity . Fisetin, luteolin, morin, quercetin, and silybin were found to be potent OAT1 inhibitors in OAT1‐expressing kidney cells (LLC‐PK1 and MDCK cells).…”

Luteolin ameliorates colistin-induced nephrotoxicity in the rat models

“…It was shown in animal experiments that renal histological abnormalities that developed due to colistin improved when used in combination with antioxidant drugs such as ascorbic acid, vitamin E, melatonin, astaxanthin, and proanthocyanidins grapeseed extracts whereas levels of free oxygen radicals decreased and apoptosis reduced. 12,13,[19][20][21] In our study, based on the study carried out by Domitrovi c et al, the main reason we selected luteolin as the active substance is because luteolin was capable of preventing cisplatin-induced nephrotoxic effect that has strongly abstained in oncology nephrotoxicity. 16 In the present study, investigators administered doses of 10 mg/kg and 20 mg/kg cisplatin and 10 mg/kg luteolin to six groups of animals that consisted of five animals in each group (together with Control Groups).…”