Document Detail

Metabolism of heterocyclic aromatic amines by human hepatocytes and cytochrome P4501A2.
MedLine Citation:
PMID:  12351158     Owner:  NLM     Status:  MEDLINE    
The metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was investigated in primary human and rat hepatocytes. The genotoxic metabolites 2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline (HONH-MeIQx) and 2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP), which are formed by cytochrome P4501A2 (CYP1A2), were detected as stable N(2)-glucuronide and N(2)- and N(3)-glucuronide conjugates, respectively. These products accounted for as much as 10% of the amount of MeIQx and 60% of PhIP added to human hepatocytes. Significantly lower amounts of these products were formed in rat hepatocytes. The phase II conjugates N(2)-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl-sulfamic acid (MeIQx-N(2)-SO(3)H) and N(2)-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx-N(2)-Gl), as well as the 7-oxo derivatives of MeIQx and N-desmethyl-MeIQx, 2-amino-3,8-dimethyl-6-hydro-7H-imidazo[4,5-f]quinoxalin-7-one (7-oxo-MeIQx), and 2-amino-6-hydro-8-methyl-7H-imidazo[4,5-f]quinoxalin-7-one (N-desmethyl-7-oxo-MeIQx) were also identified. A novel CYP1A2-derived metabolite was characterized as 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid (IQx-8-COOH) and was the predominant metabolite formed in human hepatocytes exposed to MeIQx at levels approaching human exposure. Unlike human hepatocytes, rat cell preparations, even following pretreatment with the potent CYP1A1/CYP1A2 inducer 3-methylcholanthrene (3-MC) did not produce IQx-8-COOH but did catalyze the formation of 2-amino-3,8-dimethyl-5-hydroxyimidazo[4,5-f]quinoxaline (5-HO-MeIQx) as a major CYP-mediated detoxication product. In the case of PhIP, direct glucuronidation of the N(2) and N(3) positions also occurred in human and rat hepatocytes. Glucuronide and sulfate conjugates of 2-amino-4'-hydroxy-1-methyl-6-phenylimidazo[4,5-b]pyridine (4'-HO-PhIP) were detected as relatively minor metabolites in human hepatocytes but were the major products formed in rat hepatocytes, accounting for up to 50% of the metabolism. Rat CYP1A2, but not the human ortholog, significantly contributes to 4'-hydroxylation of PhIP. Important differences exist between human and rat liver enzymes in catalytic activity and regioselectivity of MeIQx and PhIP metabolism. Some human hepatocyte preparations are more active at transforming MeIQx and PhIP to a genotoxic species than rat hepatocytes pretreated with potent inducer 3-MC. These pronounced interspecies differences in metabolism of MeIQx and PhIP may affect the biological activity of these mutagens and must be considered when assessing human health risk.
Robert J Turesky; F Peter Guengerich; André Guillouzo; Sophie Langouët
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Mutation research     Volume:  506-507     ISSN:  0027-5107     ISO Abbreviation:  Mutat. Res.     Publication Date:  2002 Sep 
Date Detail:
Created Date:  2002-09-27     Completed Date:  2002-11-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0400763     Medline TA:  Mutat Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  187-95     Citation Subset:  IM    
National Center for Toxicological Research, 3900 NCTR DR, HFT 100 Jefferson, AR 72079-9502, USA.
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MeSH Terms
Carcinogens / metabolism*
Cells, Cultured
Chromatography, High Pressure Liquid
Cytochrome P-450 CYP1A2 / metabolism*
Dose-Response Relationship, Drug
Hepatocytes / drug effects,  metabolism*
Imidazoles / metabolism*
Liver / drug effects,  metabolism
Quinoxalines / metabolism*
Rats, Sprague-Dawley
Species Specificity
Theophylline / analogs & derivatives*,  pharmacology
Reg. No./Substance:
0/Carcinogens; 0/Imidazoles; 0/Quinoxalines; 105650-23-5/2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; 58-55-9/Theophylline; 77500-04-0/2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; 80288-49-9/furafylline; EC P-450 CYP1A2

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