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Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers

  • Robert J. Fontana*
    Affiliations
    *Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Environmental Health Science, Columbia University, New York, New York; §Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California; and Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina
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  • Kenneth S. Lown*
    Affiliations
    *Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Environmental Health Science, Columbia University, New York, New York; §Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California; and Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina
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  • Mary F. Paine*
    Affiliations
    *Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Environmental Health Science, Columbia University, New York, New York; §Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California; and Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina
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  • Laurie Fortlage*
    Affiliations
    *Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Environmental Health Science, Columbia University, New York, New York; §Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California; and Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina
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  • Regina M. Santella
    Affiliations
    *Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Environmental Health Science, Columbia University, New York, New York; §Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California; and Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina
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  • James S. Felton§
    Affiliations
    *Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Environmental Health Science, Columbia University, New York, New York; §Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California; and Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina
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  • Mark G. Knize§
    Affiliations
    *Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Environmental Health Science, Columbia University, New York, New York; §Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California; and Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina
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  • Arthur Greenberg
    Affiliations
    *Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Environmental Health Science, Columbia University, New York, New York; §Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California; and Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina
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  • Paul B. Watkins*
    Affiliations
    *Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Environmental Health Science, Columbia University, New York, New York; §Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California; and Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina
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      Abstract

      Background & Aims: Carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons present in chargrilled meat are substrates for inducible CYP1A and CYP3A enzymes and for P-glycoprotein. We examined whether consumption of a chargrilled meat diet results in induction of these proteins. Methods: Ten healthy adults were fed a diet enriched with chargrilled meat for 7 days. Duodenal biopsy specimens were obtained on days 1, 5, and 12 and analyzed for CYP1A, CYP3A, and P-glycoprotein messenger RNA (mRNA) and protein. On days 5 and 12, hepatic CYP3A4 and CYP1A2 activities were measured and colon biopsies were performed. The levels of polycyclic aromatic hydrocarbon DNA adducts in peripheral blood mononuclear cells were measured on days 1, 4, 11, and 26. Results: There was no detectable induction of CYP3A4, CYP3A5, or P-glycoprotein mRNAs or protein in small intestine or colon and no induction of hepatic CYP3A4 enzyme activity. In contrast, the chargrilled meat diet resulted in unequivocal induction of CYP1A enzymes in the liver and small intestine of each subject. There was an inverse correlation between the level of peripheral polycyclic aromatic hydrocarbon DNA adducts measured on day 11 and both liver CYP1A2 activity (P = 0.027) and enterocyte CYP1A1 protein concentration (P = 0.046). Conclusions: Ingestion of chargrilled meat results in induction of CYP1A enzymes but not CYP3A4 or P-glycoprotein. This observation, combined with the correlation between adduct levels and CYP1A expression, supports an adaptive role for CYP1A but not CYP3A4 or P-glycoprotein.
      GASTROENTEROLOGY 1999;117:89-98

      Abbreviations:

      AαC (2-amino-9H-pyrido[2,3,b]indole), B(a)P (benzo[a]pyrene), bp (base pair), CBT ([13C-3-methyl]caffeine breath test), DiMelQx (2-amino-3,4,8-trimethylimidazo[4,5-f ]quinoxaline), ERMBT ([14C-N-methyl]erythromycin breath test), EROD (7-ethoxyresorufin O-deethylase), GCRC (University of Michigan General Clinical Research Center), HA (heterocyclic amine), IQ (2-amino-3-methylimidazo[4,5-f ]quinoline), MelQx (2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline), NIH (National Institutes of Health), PAH (polycyclic aromatic hydrocarbon), PCR (polymerase chain reaction), Pgp (P-glycoprotein), PhlP (2-amino-1-methyl-6-phenylimidazo[4,5-f ]pyridine)
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