The effects of heavy metal ions, phthalates and ochratoxin A on oxidation of carcinogenic aristolochic acid I causing Balkan endemic nephropathy
Language English Country Sweden Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
14329
Cancer Research UK - United Kingdom
PubMed
26757129
PII: NEL360915A01
Knihovny.cz E-resources
- MeSH
- Arsenic pharmacology MeSH
- Balkan Nephropathy * MeSH
- Ions MeSH
- Microsomes, Liver metabolism MeSH
- Cadmium pharmacology MeSH
- Carcinogens metabolism MeSH
- Rats MeSH
- Aristolochic Acids metabolism MeSH
- Phthalic Acids pharmacology MeSH
- Ochratoxins pharmacology MeSH
- Lead pharmacology MeSH
- Oxidation-Reduction drug effects MeSH
- Selenium pharmacology MeSH
- Metals, Heavy pharmacology MeSH
- Chromatography, High Pressure Liquid MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- aristolochic acid I MeSH Browser
- Arsenic MeSH
- Ions MeSH
- Cadmium MeSH
- Carcinogens MeSH
- Aristolochic Acids MeSH
- Phthalic Acids MeSH
- ochratoxin A MeSH Browser
- Ochratoxins MeSH
- Lead MeSH
- Selenium MeSH
- Metals, Heavy MeSH
OBJECTIVES: 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. CONCLUSION: 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.
Department of Biochemistry Faculty of Science Charles University Prague Czech Republic
Division of Molecular Toxicology German Cancer Research Center Heidelberg Germany
Balkan endemic nephropathy: an update on its aetiology
