{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:46:57Z","timestamp":1791978417580,"version":"4.4.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,5,3]],"date-time":"2020-05-03T00:00:00Z","timestamp":1588464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81673523"],"award-info":[{"award-number":["81673523"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Important Drug Development Fund"},{"name":"Ministry of Science and Technology of China","award":["2018ZX09201011"],"award-info":[{"award-number":["2018ZX09201011"]}]},{"name":"Ministry of Science and Technology of China","award":["2018ZX09711001-009-010"],"award-info":[{"award-number":["2018ZX09711001-009-010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Organic anion transporters 1 and 3 (OAT1 and OAT3) play a critical role in renal drug-drug interactions and are involved in the nephrotoxicity of many anionic xenobiotics. To date, relatively little is known about the interaction of natural compounds with OAT1 and OAT3. Of the 270 natural compounds screened in the present study, 21 compounds inhibited OAT1 and 45 compounds inhibited OAT3. Further concentration-dependent studies identified 7 OAT1 inhibitors and 10 OAT3 inhibitors with IC50 values of &amp;lt;10\u2009\u03bcM, and most of them were flavonoids, the most commonly ingested polyphenolic compounds in the diet and herbal products. Computational modeling of OAT1 and OAT3 revealed the important residues for the recognition of inhibitors. The two strong\u00a0OAT inhibitors, namely wedelolactone and wogonin, were evaluated for their in vivo interactions with the OAT substrate aristolochic acid I (AAI), a natural compound causing aristolochic acid-induced nephropathy (AAN) in many species. The cytotoxicity of AAI increased in two OAT-overexpressing cell lines, with more cytotoxicity in OAT1-overexpressing cells, suggesting a more important role of OAT1 than OAT3 in AAN. Both wedelolactone and wogonin markedly increased serum AAI concentrations in AAI-treated rats and ameliorated kidney injuries in AAI-treated mice. To conclude, the present findings are of significant value in understanding natural compound-drug interactions and provide a natural source for developing treatments for AAN.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa033","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T12:25:52Z","timestamp":1583497552000},"page":"279-291","source":"Crossref","is-referenced-by-count":33,"title":["Potent Inhibitors of Organic Anion Transporters 1 and 3 From Natural Compounds and Their Protective Effect on Aristolochic Acid Nephropathy"],"prefix":"10.1093","volume":"175","author":[{"given":"Caiyu","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajuan","family":"Bi","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heshui","family":"Yu","sequence":"first","affiliation":[{"name":"Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 300193, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wei","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"first","affiliation":[{"name":"Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 300193, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifeng","family":"Han","sequence":"first","affiliation":[{"name":"Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 300193, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youcai","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,3]]},"reference":[{"key":"2020052717295701000_kfaa033-B1","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1124\/dmd.114.059337","article-title":"Flavonoids are inhibitors of human organic anion transporter 1 (OAT1)-mediated transport","volume":"42","author":"An","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"2020052717295701000_kfaa033-B2","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.tox.2009.07.014","article-title":"Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy","volume":"264","author":"Bakhiya","year":"2009","journal-title":"Toxicology"},{"key":"2020052717295701000_kfaa033-B3","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/ki.2012.264","article-title":"Probenecid prevents acute tubular necrosis in a mouse model of aristolochic acid nephropathy","volume":"82","author":"Baudoux","year":"2012","journal-title":"Kidney Int."},{"key":"2020052717295701000_kfaa033-B4","doi-asserted-by":"crossref","first-page":"14417","DOI":"10.1074\/jbc.M112.442970","article-title":"Wedelolactone, a naturally occurring coumestan, enhances interferon-gamma signaling through inhibiting STAT1 protein dephosphorylation","volume":"288","author":"Chen","year":"2013","journal-title":"J. Biol. Chem."},{"key":"2020052717295701000_kfaa033-B5","doi-asserted-by":"crossref","first-page":"e4191","DOI":"10.1002\/bmc.4191","article-title":"Validated UPLC-MS\/MS method for quantification of seven compounds in rat plasma and tissues: Application to pharmacokinetic and tissue distribution studies in rats after oral administration of extract of Eclipta prostrata L","volume":"32","author":"Du","year":"2018","journal-title":"Biomed. Chromatogr"},{"key":"2020052717295701000_kfaa033-B6","doi-asserted-by":"crossref","first-page":"3340","DOI":"10.1021\/mp300365t","article-title":"Potent inhibitors of human organic anion transporters 1 and 3 from clinical drug libraries: discovery and molecular characterization","volume":"9","author":"Duan","year":"2012","journal-title":"Mol. Pharm."},{"key":"2020052717295701000_kfaa033-B7","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1152\/physiolgenomics.00207.2007","article-title":"Multiple organic anion transporters contribute to net renal excretion of uric acid","volume":"33","author":"Eraly","year":"2008","journal-title":"Physiol. Genomics"},{"key":"2020052717295701000_kfaa033-B8","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.chroma.2018.11.024","article-title":"Simultaneously targeted and untargeted multicomponent characterization of Erzhi Pill by offline two-dimensional liquid chromatography\/quadrupole-Orbitrap mass spectrometry","volume":"1584","author":"Fu","year":"2019","journal-title":"J. Chromatogr. A"},{"key":"2020052717295701000_kfaa033-B9","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.clpt.2003.08.009","article-title":"The interaction between St John\u2019s wort and an oral contraceptive","volume":"74","author":"Hall","year":"2003","journal-title":"Clin. Pharmacol. Ther."},{"key":"2020052717295701000_kfaa033-B10","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S1674-6384(13)60047-7","article-title":"Chemical constituents from dried aerial parts of Eclipta prostrata","volume":"5","author":"Han","year":"2013","journal-title":"Chin. Herb. Med"},{"key":"2020052717295701000_kfaa033-B11","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1080\/14786419.2014.998216","article-title":"Triglyceride accumulation inhibitory effects of new chromone glycosides from Drynaria fortunei","volume":"29","author":"Han","year":"2015","journal-title":"Nat. Product Res."},{"key":"2020052717295701000_kfaa033-B12","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S1674-6384(14)60025-3","article-title":"Saponins from roots of Panax notoginseng","volume":"6","author":"Han","year":"2014","journal-title":"Chin. Herb. Med."},{"key":"2020052717295701000_kfaa033-B13","doi-asserted-by":"crossref","first-page":"3130","DOI":"10.1021\/acs.molpharmaceut.6b00332","article-title":"Identification and quantitative assessment of uremic solutes as inhibitors of renal organic anion transporters, OAT1 and OAT3","volume":"13","author":"Hsueh","year":"2016","journal-title":"Mol. Pharm."},{"key":"2020052717295701000_kfaa033-B14","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/ki.2011.371","article-title":"Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid","volume":"81","author":"Jelakovic","year":"2012","journal-title":"Kidney Int."},{"key":"2020052717295701000_kfaa033-B15","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/sj.cdd.4401325","article-title":"Wedelolactone suppresses LPS-induced caspase-11 expression by directly inhibiting the IKK Complex","volume":"11","author":"Kobori","year":"2004","journal-title":"Cell Death Differ."},{"key":"2020052717295701000_kfaa033-B16","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/BF00228148","article-title":"AQUA and PROCHECK-NMR: Programs for checking the quality of protein structures solved by NMR","volume":"8","author":"Laskowski","year":"1996","journal-title":"J. Biomol. NMR"},{"key":"2020052717295701000_kfaa033-B17","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jchromb.2019.02.001","article-title":"Enhanced identification of the in vivo metabolites of Ecliptae Herba in rat plasma by integrating untargeted data-dependent MS2 and predictive multiple reaction monitoring-information dependent acquisition-enhanced product ion scan","volume":"1109","author":"Li","year":"2019","journal-title":"J. Chromatogr. B"},{"key":"2020052717295701000_kfaa033-B18","doi-asserted-by":"crossref","first-page":"3436","DOI":"10.1002\/jcb.24220","article-title":"Wedelolactone inhibits adipogenesis through the ERK pathway in human adipose tissue-derived mesenchymal stem cells","volume":"113","author":"Lim","year":"2012","journal-title":"J. Cell Biochem."},{"key":"2020052717295701000_kfaa033-B19","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.clpt.2004.07.004","article-title":"Hyperforin content determines the magnitude of the St John\u2019s wort-cyclosporine drug interaction","volume":"76","author":"Mai","year":"2004","journal-title":"Clin. Pharmacol. Ther."},{"key":"2020052717295701000_kfaa033-B20","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1056\/NEJM200006083422301","article-title":"Urothelial carcinoma associated with the use of a Chinese herb","volume":"342","author":"Nortier","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"2020052717295701000_kfaa033-B21","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1080\/10286020.2018.1478816","article-title":"Two new naphthalene glycosides from the seeds of Cassia obtusifolia","volume":"21","author":"Pang","year":"2018","journal-title":"J. Asian Nat. Prod. Res."},{"key":"2020052717295701000_kfaa033-B22","doi-asserted-by":"crossref","first-page":"3409","DOI":"10.1080\/14786419.2018.1480621","article-title":"New anthraquinone and eurotinone analogue from the seeds of Senna obtusifolia and their inhibitory effects on human organic anion transporters 1 and 3","volume":"33","author":"Pang","year":"2018","journal-title":"Nat. Prod. Res."},{"key":"2020052717295701000_kfaa033-B23","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1080\/14786419.2017.1405410","article-title":"Prenylated flavonoids and dihydrophenanthrenes from the leaves of Epimedium brevicornu and their\u00a0cytotoxicity\u00a0against HepG2 cells","volume":"32","author":"Pang","year":"2018","journal-title":"Nat. Prod. Res."},{"key":"2020052717295701000_kfaa033-B24","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1016\/j.bmcl.2018.03.080","article-title":"Secoiridoid analogues from the fruits of Ligustrum lucidum and their inhibitory activities against influenza A virus","volume":"28","author":"Pang","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2020052717295701000_kfaa033-B25","doi-asserted-by":"crossref","first-page":"38071","DOI":"10.1074\/jbc.M608834200","article-title":"A three-dimensional model of human organic anion transporter 1: Aromatic amino acids required for substrate transport","volume":"281","author":"Perry","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2020052717295701000_kfaa033-B26","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.jpba.2017.02.048","article-title":"Modeling and optimizing inhibitory activities of Nelumbinis folium extract on xanthine oxidase using response surface methodology","volume":"139","author":"Sang","year":"2017","journal-title":"J. Pharm. Biomed. Anal."},{"key":"2020052717295701000_kfaa033-B27","doi-asserted-by":"crossref","first-page":"2073S","DOI":"10.1093\/jn\/130.8.2073S","article-title":"Dietary intake and bioavailability of polyphenols","volume":"130(8S Suppl","author":"Scalbert","year":"2000","journal-title":"J. Nutr."},{"key":"2020052717295701000_kfaa033-B28","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1124\/jpet.300.3.918","article-title":"Human organic anion transporters and human organic cation transporters mediate renal antiviral transport","volume":"300","author":"Takeda","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2020052717295701000_kfaa033-B29","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/clpt.2013.77","article-title":"Transporter studies in drug development: experience to date and follow-up on decision trees from the International Transporter Consortium","volume":"94","author":"Tweedie","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"2020052717295701000_kfaa033-B30","doi-asserted-by":"crossref","first-page":"16454","DOI":"10.3390\/ijms160716454","article-title":"Baicalin protects mice from aristolochic acid I-induced kidney injury by induction of CYP1A through the aromatic hydrocarbon receptor","volume":"16","author":"Wang","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"2020052717295701000_kfaa033-B31","first-page":"612527","article-title":"Interaction of natural dietary and herbal anionic compounds and flavonoids with human organic anion transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11)","volume":"2013","author":"Wang","year":"2013","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"2020052717295701000_kfaa033-B32","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.phytol.2019.05.010","article-title":"Glycosidic compounds from Cassia obtusifolia seeds and their inhibitory effects on OATs, OCTs and OATPs","volume":"32","author":"Wang","year":"2019","journal-title":"Phytochemistry Letters"},{"key":"2020052717295701000_kfaa033-B33","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1093\/toxsci\/kfx216","article-title":"From the cover: Identification of natural products as inhibitors of human organic anion transporters (OAT1 and OAT3) and their protective effect on mercury-induced toxicity","volume":"161","author":"Wang","year":"2018","journal-title":"Toxicol. Sci."},{"key":"2020052717295701000_kfaa033-B34","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: Homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2020052717295701000_kfaa033-B35","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1124\/dmd.105.004275","article-title":"The dietary polyphenol ellagic acid is a potent inhibitor of hOAT1","volume":"33","author":"Whitley","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"2020052717295701000_kfaa033-B36","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.bcp.2011.01.004","article-title":"Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1\/SLC22A6)","volume":"81","author":"Wong","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"2020052717295701000_kfaa033-B37","doi-asserted-by":"crossref","first-page":"4939","DOI":"10.1038\/s41598-017-04949-2","article-title":"Key role for the organic anion transporters, OAT1 and OAT3, in the in vivo handling of uremic toxins and solutes","volume":"7","author":"Wu","year":"2017","journal-title":"Sci. Rep."},{"key":"2020052717295701000_kfaa033-B38","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1038\/aps.2009.156","article-title":"beta-Naphthoflavone protects mice from aristolochic acid-I-induced acute kidney injury in a CYP1A dependent mechanism","volume":"30","author":"Xiao","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"2020052717295701000_kfaa033-B39","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1021\/mp100418u","article-title":"Critical role of organic anion transporters 1 and 3 in kidney accumulation and toxicity of aristolochic acid I","volume":"8","author":"Xue","year":"2011","journal-title":"Mol. Pharm."},{"key":"2020052717295701000_kfaa033-B40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/625601","article-title":"Chinese herbs containing aristolochic acid associated with renal failure and urothelial carcinoma: A review from epidemiologic observations to causal inference","volume":"2014","author":"Yang","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"2020052717295701000_kfaa033-B41","doi-asserted-by":"crossref","first-page":"e1283","DOI":"10.1038\/cddis.2014.221","article-title":"NF-kappaB and Nrf2 signaling pathways contribute to wogonin-mediated inhibition of inflammation-associated colorectal carcinogenesis","volume":"5","author":"Yao","year":"2014","journal-title":"Cell Death Dis."},{"key":"2020052717295701000_kfaa033-B42","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.fitote.2016.10.011","article-title":"Bioactive constituents from the rhizomes of Dioscorea septemloba Thunb","volume":"115","author":"Zhang","year":"2016","journal-title":"Fitoterapia"},{"key":"2020052717295701000_kfaa033-B43","doi-asserted-by":"crossref","first-page":"10352","DOI":"10.3390\/molecules180910352","article-title":"Bioactive protopanaxatriol type saponins isolated from the roots of Panax notoginseng (Burk.) F. H. Chen","volume":"18","author":"Zhang","year":"2013","journal-title":"Molecules"},{"key":"2020052717295701000_kfaa033-B44","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.cmpb.2010.01.007","article-title":"PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel","volume":"99","author":"Zhang","year":"2010","journal-title":"Comput. Methods Programs Biomed."},{"key":"2020052717295701000_kfaa033-B45","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.fitote.2017.01.004","article-title":"Bioactive diarylheptanoids and stilbenes from the rhizomes of Dioscorea septemloba Thunb","volume":"117","author":"Zhang","year":"2017","journal-title":"Fitoterapia"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfaa033\/33157954\/kfaa033.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/toxsci\/article-pdf\/175\/2\/279\/33316847\/kfaa033.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/toxsci\/article-pdf\/175\/2\/279\/33316847\/kfaa033.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T21:31:09Z","timestamp":1590615069000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/175\/2\/279\/5803092"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,3]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,5,3]]},"published-print":{"date-parts":[[2020,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfaa033","relation":{},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,6]]},"published":{"date-parts":[[2020,5,3]]}}}