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Rapid CommunicationShort Communication

Effect of Hepatic Cytochrome P450 (P450) Oxidoreductase Deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 Reductase Conditional Null Mice

Volker M. Arlt, Rajinder Singh, Marie Stiborová, Gonçalo Gamboa da Costa, Eva Frei, James D. Evans, Peter B. Farmer, C. Roland Wolf, Colin J. Henderson and David H. Phillips
Drug Metabolism and Disposition December 2011, 39 (12) 2169-2173; DOI: https://doi.org/10.1124/dmd.111.041343
Volker M. Arlt
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Rajinder Singh
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Marie Stiborová
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Gonçalo Gamboa da Costa
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Eva Frei
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James D. Evans
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Peter B. Farmer
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C. Roland Wolf
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Colin J. Henderson
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David H. Phillips
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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 cytochromes P450 (P450s). To evaluate the role of hepatic P450s in the bioactivation of PhIP, we used Reductase Conditional Null (RCN) mice, in which cytochrome P450 oxidoreductase (POR), the unique electron donor to P450s, can be specifically deleted in hepatocytes by pretreatment with 3-methylcholanthrene (3-MC), resulting in the loss of essentially all hepatic P450 function. RCN mice were treated orally with 50 mg/kg b.wt. 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/108 deoxynucleosides), whereas adduct levels in liver were ∼3.5-fold lower. Whereas 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 extrahepatic 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 extrahepatic tissues, and further activation, resulting in the formation of dG-C8-PhIP. Besides hepatic P450s, PhIP may be metabolically activated mainly by a non-P450 pathway in liver.

Footnotes

  • This work was supported by Environmental Cancer Risk, Nutrition and Individual Susceptibility as part of the European Union 6th Framework, Priority 5: “Food Quality and Safety” [Contract 513943]; Cancer Research UK; and the Grant Agency of the Czech Republic [Grant P301/10/0356].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.041343.

  • ABBREVIATIONS:

    HAA
    heterocyclic aromatic amine
    PhIP
    2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
    P450
    cytochrome P450
    dG-C8-PhIP
    N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
    RCN
    Reductase Conditional Null
    POR
    cytochrome P450 oxidoreductase
    3-MC
    3-methylcholanthrene
    ESI
    electrospray ionization
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    α-NF
    α-naphthoflavone
    HRN
    Hepatic P450 Reductase Null
    PTGS
    prostaglandin H synthase.

  • Received June 23, 2011.
  • Accepted September 22, 2011.
  • U.S. Government work not protected by U.S. copyright
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Drug Metabolism and Disposition: 39 (12)
Drug Metabolism and Disposition
Vol. 39, Issue 12
1 Dec 2011
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Rapid CommunicationShort Communication

DETECTION OF PhIP-DNA ADDUCTS IN RCN MICE

Volker M. Arlt, Rajinder Singh, Marie Stiborová, Gonçalo Gamboa da Costa, Eva Frei, James D. Evans, Peter B. Farmer, C. Roland Wolf, Colin J. Henderson and David H. Phillips
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2169-2173; DOI: https://doi.org/10.1124/dmd.111.041343

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Rapid CommunicationShort Communication

DETECTION OF PhIP-DNA ADDUCTS IN RCN MICE

Volker M. Arlt, Rajinder Singh, Marie Stiborová, Gonçalo Gamboa da Costa, Eva Frei, James D. Evans, Peter B. Farmer, C. Roland Wolf, Colin J. Henderson and David H. Phillips
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2169-2173; DOI: https://doi.org/10.1124/dmd.111.041343
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