Journal article
Flavonoids are inhibitors of human organic anion transporter 1 (OAT1)-mediated transport
Drug metabolism and disposition, Vol.42(9), pp.1357-1366
09/2014
DOI: 10.1124/dmd.114.059337
PMCID: PMC4152875
PMID: 25002746
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 μM. Further concentration-dependent studies revealed that both morin and luteolin are potent OAT1 inhibitors, with IC50 values of <0.3 and 0.47 μM, 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.
Details
- Title: Subtitle
- Flavonoids are inhibitors of human organic anion transporter 1 (OAT1)-mediated transport
- Creators
- Guohua An - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, University at Buffalo, Buffalo, New YorkXiaodong Wang - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, University at Buffalo, Buffalo, New YorkMarilyn E Morris - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, University at Buffalo, Buffalo, New York memorris@buffalo.edu
- Resource Type
- Journal article
- Publication Details
- Drug metabolism and disposition, Vol.42(9), pp.1357-1366
- Publisher
- United States
- DOI
- 10.1124/dmd.114.059337
- PMID
- 25002746
- PMCID
- PMC4152875
- ISSN
- 0090-9556
- eISSN
- 1521-009X
- Grant note
- R01 DA023223 / NIDA NIH HHS R01-DA023223 / NIDA NIH HHS
- Language
- English
- Date published
- 09/2014
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984065695302771
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