Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy.

2.50
Hdl Handle:
http://hdl.handle.net/10146/114684
Title:
Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy.
Authors:
Bakhiya, Nadiya; Arlt, Volker M.; Bahn, Andrew; Burckhardt, Gerhard; Phillips, David H.; Glatt, Hansruedi
Abstract:
Aristolochic 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.
Citation:
Toxicology 2009, 264 (1-2):74-79
Journal:
Toxicology
Issue Date:
1-Oct-2009
URI:
http://hdl.handle.net/10146/114684
DOI:
10.1016/j.tox.2009.07.014
PubMed ID:
19643159
Additional Links:
http://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=a
Type:
Article
Language:
en
ISSN:
1879-3185
Sponsors:
We 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).
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorBakhiya, Nadiyaen
dc.contributor.authorArlt, Volker M.en
dc.contributor.authorBahn, Andrewen
dc.contributor.authorBurckhardt, Gerharden
dc.contributor.authorPhillips, David H.en
dc.contributor.authorGlatt, Hansruedien
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.en
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

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