Human cytochromes P450 1A1 and 1A2 participate in detoxication of carcinogenic aristolochic acid
Language English Country Sweden Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
18987598
PII: NEL290508A20
Knihovny.cz E-resources
- MeSH
- Cytochrome P-450 CYP1A1 isolation & purification metabolism MeSH
- Cytochrome P-450 CYP1A2 isolation & purification metabolism MeSH
- Microsomes, Liver enzymology MeSH
- Carcinogens pharmacokinetics MeSH
- Rats MeSH
- Aristolochic Acids pharmacokinetics MeSH
- Humans MeSH
- Inactivation, Metabolic MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Chromatography, High Pressure Liquid MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- aristolochic acid I MeSH Browser
- Cytochrome P-450 CYP1A1 MeSH
- Cytochrome P-450 CYP1A2 MeSH
- Carcinogens MeSH
- Aristolochic Acids MeSH
OBJECTIVES: A carcinogenic and nephrotoxic plant alkaloid, aristolochic acid (AA), causes the development of aristolochic acid nephropathy, which is characterized by chronic renal failure, tubulointerstitial fibrosis and urothelial cancer. AA may also cause a similar type of kidney fibrosis with malignant transformation of the urothelium, the Balkan endemic nephropathy. The aim of the study was to resolve which cytochromes P450 (CYP) detoxicate the major component of AA, aristolochic acid I (AAI), to its O-demethylated metabolite, aristolochic acid Ia (AAIa). METHODS: High performance liquid chromatography (HPLC) was employed for separation and characterization of AAI metabolites generated by CYPs. RESULTS: Human, rat and mouse hepatic CYPs oxidize AAI into its detoxication metabolite AAIa. Most of the detoxication of AAI in human hepatic microsomes is mediated by CYP1A2 and 1A1, while other CYPs play a minor role. CONCLUSIONS: The data are the first report on identification of human CYP enzymes detoxicating AAI.
Balkan endemic nephropathy: an update on its aetiology
