The effects of heavy metal ions, phthalates and ochratoxin A on oxidation of carcinogenic aristolochic acid I causing Balkan endemic nephropathy.

Abstract

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.

• Authors: Frantisek Barta, Katerina Levova, Petr Hodek, Heinz H Schmeiser, Volker M Arlt, Marie Stiborova
• Journal: Neuro endocrinology letters (Neuro Endocrinol Lett) Vol. 36 Suppl 1 Pg. 13-21 ( 2015) ISSN: 0172-780X [Print] Sweden
• PMID: 26757129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aristolochic Acids
• Carcinogens
• Ions
• Metals, Heavy
• Ochratoxins
• Phthalic Acids
• Cadmium
• ochratoxin A
• Lead
• aristolochic acid I
• Selenium
• Arsenic

Topics

• Animals
• Aristolochic Acids (metabolism)
• Arsenic (pharmacology)
• Balkan Nephropathy
• Cadmium (pharmacology)
• Carcinogens (metabolism)
• Chromatography, High Pressure Liquid
• Ions
• Lead (pharmacology)
• Metals, Heavy (pharmacology)
• Microsomes, Liver (metabolism)
• Ochratoxins (pharmacology)
• Oxidation-Reduction (drug effects)
• Phthalic Acids (pharmacology)
• Rats
• Selenium (pharmacology)