title: The influence of ochratoxin A on DNA adduct formation by the carcinogen aristolochic acid in rats.
abstract: Exposure to the plant nephrotoxin and carcinogen aristolochic acid (AA) leads to the development of AA nephropathy, Balkan endemic nephropathy (BEN) and upper urothelial carcinoma (UUC) in humans. Beside AA, exposure to ochratoxin A (OTA) was linked to BEN. Although OTA was rejected as a factor for BEN/UUC, there is still no information whether the development of AA-induced BEN/UUC is influenced by OTA exposure. Therefore, we studied the influence of OTA on the genotoxicity of AA (AA-DNA adduct formation) in vivo. AA-DNA adducts were formed in liver and kidney of rats treated with AA or AA combined with OTA, but no OTA-related DNA adducts were detectable in rats treated with OTA alone or OTA combined with AA. Compared to rats treated with AA alone, AA-DNA adduct levels were 5.4- and 1.6-fold higher in liver and kidney, respectively, of rats treated with AA combined with OTA. Although AA and OTA induced
  quinone oxidoreductase (NQO1) activating AA to DNA adducts, their combined treatment did not lead to either higher NQO1 enzyme activity or higher AA-DNA adduct levels in ex vivo incubations. Oxidation of AA I (8-methoxy-6-nitrophenanthro[3,4-d]-1,3-dioxole-5-carboxylic acid) to its detoxification metabolite, 8-hydroxyaristolochic acid, was lower in microsomes from rats treated with AA and OTA, and this was paralleled by lower activities of cytochromes P450 1A1/2 and/or 2C11 in these microsomes. Our results indicate that a decrease in AA detoxification after combined exposure to AA and OTA leads to an increase in AA-DNA adduct formation in liver and kidney of rats.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40, Prague 2, Czech Republic. stiborov@natur.cuni.cz.
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborová
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40, Prague 2, Czech Republic.
authors.forename: František
authors.initials: F
authors.lastname: Bárta
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40, Prague 2, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Levová
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40, Prague 2, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Hodek
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environmental and Health, King's College London, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: Division of Radiopharmaceutical Chemistry (E030), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D018736:DNA Adducts / Q000187:drug effects*; D008658:Inactivation, Metabolic / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009793:Ochratoxins / Q000494:pharmacology*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D018736:DNA Adducts; D009793:Ochratoxins; C025589:ochratoxin A; C000228:aristolochic acid I; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat
keywords: Aristolochic acid; Aristolochic acid nephropathy; Balkan endemic nephropathy; DNA adducts; Ochratoxin A