Document Detail


Human cytochromes P450 1A1 and 1A2 participate in detoxication of carcinogenic aristolochic acid.
MedLine Citation:
PMID:  18987598     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Jana Sistkova; Jiri Hudecek; Petr Hodek; Eva Frei; Heinz H Schmeiser; Marie Stiborova
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Neuro endocrinology letters     Volume:  29     ISSN:  0172-780X     ISO Abbreviation:  Neuro Endocrinol. Lett.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-11-25     Completed Date:  2009-02-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8008373     Medline TA:  Neuro Endocrinol Lett     Country:  Sweden    
Other Details:
Languages:  eng     Pagination:  733-7     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aristolochic Acids / pharmacokinetics*
Carcinogens / pharmacokinetics*
Chromatography, High Pressure Liquid
Cytochrome P-450 CYP1A1 / isolation & purification,  metabolism*
Cytochrome P-450 CYP1A2 / isolation & purification,  metabolism*
Humans
Metabolic Detoxication, Drug
Mice
Mice, Inbred C57BL
Microsomes, Liver / enzymology
Rats
Chemical
Reg. No./Substance:
0/Aristolochic Acids; 0/Carcinogens; 313-67-7/aristolochic acid I; EC 1.14.14.1/Cytochrome P-450 CYP1A1; EC 1.14.14.1/Cytochrome P-450 CYP1A2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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