title: The effects of heavy metal ions, phthalates and ochratoxin A on oxidation of carcinogenic aristolochic acid I causing Balkan endemic nephropathy.
abstract: OBJECTIVE
  Balkan endemic nephropathy (BEN) is a chronic progressive fibrosis associated with upper urothelial carcinoma (UUC). Aetiology of BEN is still not fully explained. Although carcinogenic aristolochic acid I (AAI) was proven as the major cause of BEN/UUC, this nephropathy is considered to be multifactorial. Hence, we investigated whether other factors considered as potential causes of BEN [a mycotoxin ochratoxin A (OTA), Cd, Pb, Se and As ions and organic compounds (i.e. phthalates) released from lignite deposits in BEN areas] can influence detoxication of AAI, whose concentrations are crucial for BEN development.
  
  
  METHODS
  Oxidation of AAI to 8-hydroxyaristolochic acid I (AAIa) in the presence of Cd, Pb, Se, As ions, dibutylphthalate (DBP), butylbenzylphthalate (BBP), bis(2-ethylhexyl)phthalate (DEHP) and OTA by rat liver microsomes was determined by HPLC.
  
  
  RESULTS
  Only OTA, cadmium and selenium ions, and BBP inhibited AAI oxidation by rat liver microsomes. These compounds also inhibited activities of CYP1A1 and/or CYP2C6/11 catalysing AAI demethylation in rat livers. Therefore, these CYP inhibitions can be responsible for a decrease in AAIa formation. When the combined effects of these compounds were investigated, the most efficient inhibition was caused by OTA combined with BBP and selenium ions.
  
  
  CONCLUSIONS
  The results show low effects of BBP, cadmium and selenium ions, and/or their combinations on AAI detoxication. No effects were produced by the other metal ions (Pb, As) and phthalates DBP and DEHP. This finding suggests that they do not influence AAI-mediated BEN development. In contrast, OTA might influence this process, by inhibition of AAI detoxication.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Barta
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Levova
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Hodek
authors.affiliation: Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, London, UK.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborova
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000378:metabolism*; D001151:Arsenic / Q000494:pharmacology; D001449:Balkan Nephropathy; D002104:Cadmium / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D007477:Ions; D007854:Lead / Q000494:pharmacology; D019216:Metals, Heavy / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D009793:Ochratoxins / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects*; D010795:Phthalic Acids / Q000494:pharmacology*; D051381:Rats; D012643:Selenium / Q000494:pharmacology
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D007477:Ions; D019216:Metals, Heavy; D009793:Ochratoxins; D010795:Phthalic Acids; D002104:Cadmium; C025589:ochratoxin A; D007854:Lead; C000228:aristolochic acid I; D012643:Selenium; D001151:Arsenic