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    Effect of hepatic cytochrome P450 oxidoreductase deficiency on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adduct formation in P450 reductase conditional null mice.

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    Authors
    Arlt, Volker M.
    Singh, Rajinder
    Stiborova, Marie
    Gamboa da Costa, Goncalo
    Frei, Eva
    Evans, James D.
    Farmer, Peter B.
    Wolf, C. Roland
    Henderson, Colin J.
    Phillips, David H.
    Issue Date
    2011-09-22
    
    Metadata
    Show full item record
    Abstract
    2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), formed during the cooking of foods, induces colon cancer in rodents. PhIP is metabolically activated by cytochrome P450s (CYPs). In order to evaluate the role of hepatic CYPs in the bioactivation of PhIP, we used Reductase Conditional Null (RCN) mice, in which cytochrome P450 oxidoreductase (POR), the unique electron donor to CYPs, can be specifically deleted in hepatocytes by pretreatment with 3-methylcholanthrene (3-MC), resulting in the loss of essentially all hepatic CYP function. RCN mice were treated orally with 50 mg/kg body weight PhIP daily for 5 days, with and without 3-MC pretreatment. PhIP-DNA adducts (i.e. N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [dG-C8-PhIP]), measured by liquid chromatography-tandem mass spectrometry, were highest in colon (1362 adducts per 10(8) deoxynucleosides), while adduct levels in liver were ~3.5-fold lower. While no differences in PhIP-DNA adduct levels were found in livers with active POR versus inactivated POR, adduct levels were on average ~2-fold lower in extra-hepatic tissues of mice lacking hepatic POR. Hepatic microsomes from RCN mice with or without 3-MC pretreatment were also incubated with PhIP and DNA in vitro. PhIP-DNA adduct formation was ~8-fold lower with hepatic microsomes from POR-inactivated mice than with those with active POR. Most of the hepatic microsomal activation of PhIP in vitro was attributable to CYP1A. Our results show that PhIP-DNA adduct formation in colon involves hepatic N-oxidation, circulation of activated metabolites via the bloodstream to extra-hepatic tissues and further activation resulting in the formation of dG-C8-PhIP. Besides hepatic CYPs, PhIP may be metabolically activated mainly by a non-CYP pathway in liver.
    Citation
    Drug Metab. Dispos. 2011, 39 (12):2169-2173
    Journal
    Drug Metabolism and Disposition
    URI
    http://hdl.handle.net/10146/189938
    DOI
    10.1124/dmd.111.041343
    PubMed ID
    21940903
    Additional Links
    http://dmd.aspetjournals.org/content/early/2011/09/22/dmd.111.041343.long
    Type
    Article
    Language
    en
    ISSN
    1521-009X
    Sponsors
    This work was supported by Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS) as part of the European Union 6 th Framework, Priority 5: ‘Food Quality and Safety’ [Contract No. 513943]; Cancer Research UK; and the Grant Agency of the Czech Republic [Grant P301/10/0356]
    ae974a485f413a2113503eed53cd6c53
    10.1124/dmd.111.041343
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