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dc.contributor.authorBakhiya, Nadiya
dc.contributor.authorArlt, Volker M.
dc.contributor.authorBahn, Andrew
dc.contributor.authorBurckhardt, Gerhard
dc.contributor.authorPhillips, David H.
dc.contributor.authorGlatt, Hansruedi
dc.date.accessioned2010-11-04T11:53:28Z
dc.date.available2010-11-04T11:53:28Z
dc.date.issued2009-10-01
dc.identifier.citationToxicology 2009, 264 (1-2):74-79en
dc.identifier.issn1879-3185
dc.identifier.pmid19643159
dc.identifier.doi10.1016/j.tox.2009.07.014
dc.identifier.urihttp://hdl.handle.net/10146/114684
dc.description.abstractAristolochic acid (AA), present in Aristolochia species, is the major causative agent in the development of severe renal failure and urothelial cancers in patients with AA nephropathy. It may also be a cause of Balkan endemic nephropathy. Epithelial cells of the proximal tubule are the primary cellular target of AA. To study whether organic anion transporters (OATs) expressed in proximal tubule cells are involved in uptake of AA, we used human epithelial kidney (HEK293) cells stably expressing human (h) OAT1, OAT3 or OAT4. AA potently inhibited the uptake of characteristic substrates, p-aminohippurate for hOAT1 and estrone sulfate for hOAT3 and hOAT4. Aristolochic acid I (AAI), the more cytotoxic and genotoxic AA congener, exhibited high affinity for hOAT1 (K(i)=0.6 microM) as well as hOAT3 (K(i)=0.5 microM), and lower affinity for hOAT4 (K(i)=20.6 microM). Subsequently, AAI-DNA adduct formation (investigated by (32)P-postlabelling) was used as a measure of AAI uptake. Significantly higher levels of adducts occurred in hOAT-expressing cells than in control cells: this effect was abolished in the presence of the OAT inhibitor probenecid. In Xenopus laevis oocytes hOAT-mediated efflux of p-aminohippurate was trans-stimulated by extracellular AA, providing further molecular evidence for AA translocation by hOATs. Our study indicates that OATs can mediate the uptake of AA into proximal tubule cells and thereby participate in kidney cell damage by this toxin.
dc.description.sponsorshipWe thank Christine Gumz and Gesche Dallmeyer for skillful technical assistance. Work at the Institute of Cancer Research was supported by the Association for International Cancer Research (AICR) and Cancer Research UK. VMA and DHP are members of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a Network of Excellence operating with the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No. 513943).en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCN-4WW2SPV-2&_user=1843694&_coverDate=10%2F01%2F2009&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=bfec978711f229a31f5bbdc46ae49b6d&searchtype=aen
dc.subjectAristolochic Acidsen
dc.subjectKidney Diseasesen
dc.subjectDNA Adductsen
dc.subjectOrganic Anion Transportersen
dc.subjectHumansen
dc.subjectAnimalsen
dc.subjectCells, Cultureden
dc.subject.meshAnimals
dc.subject.meshAristolochic Acids
dc.subject.meshCells, Cultured
dc.subject.meshDNA Adducts
dc.subject.meshExtracellular Space
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshKidney
dc.subject.meshKidney Diseases
dc.subject.meshOocytes
dc.subject.meshOrganic Anion Transporters
dc.subject.meshProbenecid
dc.subject.meshRenal Agents
dc.subject.meshXenopus laevis
dc.subject.meshp-Aminohippuric Acid
dc.titleMolecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy.en
dc.typeArticleen
dc.identifier.journalToxicologyen
html.description.abstractAristolochic acid (AA), present in Aristolochia species, is the major causative agent in the development of severe renal failure and urothelial cancers in patients with AA nephropathy. It may also be a cause of Balkan endemic nephropathy. Epithelial cells of the proximal tubule are the primary cellular target of AA. To study whether organic anion transporters (OATs) expressed in proximal tubule cells are involved in uptake of AA, we used human epithelial kidney (HEK293) cells stably expressing human (h) OAT1, OAT3 or OAT4. AA potently inhibited the uptake of characteristic substrates, p-aminohippurate for hOAT1 and estrone sulfate for hOAT3 and hOAT4. Aristolochic acid I (AAI), the more cytotoxic and genotoxic AA congener, exhibited high affinity for hOAT1 (K(i)=0.6 microM) as well as hOAT3 (K(i)=0.5 microM), and lower affinity for hOAT4 (K(i)=20.6 microM). Subsequently, AAI-DNA adduct formation (investigated by (32)P-postlabelling) was used as a measure of AAI uptake. Significantly higher levels of adducts occurred in hOAT-expressing cells than in control cells: this effect was abolished in the presence of the OAT inhibitor probenecid. In Xenopus laevis oocytes hOAT-mediated efflux of p-aminohippurate was trans-stimulated by extracellular AA, providing further molecular evidence for AA translocation by hOATs. Our study indicates that OATs can mediate the uptake of AA into proximal tubule cells and thereby participate in kidney cell damage by this toxin.


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