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Research ArticleArticle

Comparative Metabolism of the Tobacco-Related Carcinogens Benzo[a]pyrene, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, andN′-Nitrosonornicotine in Human Hepatic Microsomes

Marianne E. Staretz, Sharon E. Murphy, Christopher J. Patten, Maria G. Nunes, Werner Koehl, Shantu Amin, Leeann A. Koenig, F. Peter Guengerich and Stephen S. Hecht
Drug Metabolism and Disposition February 1997, 25 (2) 154-162;
Marianne E. Staretz
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Sharon E. Murphy
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Christopher J. Patten
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Maria G. Nunes
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Werner Koehl
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Shantu Amin
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Leeann A. Koenig
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F. Peter Guengerich
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Stephen S. Hecht
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Abstract

We compared the metabolism in human hepatic microsomes of three tobacco smoke carcinogens believed to be involved in the induction of cancer in humans: benzo[a]pyrene (BaP),4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), andN′-nitrosonornicotine (NNN). The metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a major metabolite of NNK, was also investigated. Although the metabolism of some of these compounds by human enzymes or tissue preparations has been previously examined in some studies, they have never been compared in the same human hepatic samples. Moreover, there have been no previous reports of NNAL metabolism by human tissues or enzymes. The tritium-labeled carcinogens (3 μM) were incubated with 10 different human hepatic microsomal preparations and cofactors for 10–20 min, and the products were analyzed by radioflow HPLC. NNN was the best substrate for oxidative metabolism, with the 5′-hydroxylation pathway being the predominant one observed (mean ± SD = 31 ± 17 pmol/min/mg protein). α-Hydroxylation of NNK by the methylene and methyl hydroxylation metabolic activation pathways was the next fastest reaction, with rates of 3.1 ± 1.9 and 3.3 ± 1.1 pmol/min/mg protein, respectively. Metabolism of BaP resulted in the formation of dihydrodiols and phenols;trans-7,8-dihydro-7,8-dihydroxy-BaP, its major proximate carcinogen, was formed at a rate of 1.1 ± 0.61 pmol/min/mg protein. α-Hydroxylation of NNAL proceeded at a rate of 0.53 ± 0.26 pmol/min/mg protein. The results of this study demonstrate that human hepatic microsomes metabolize all of these tobacco carcinogens resulting in a substantial stream of electrophilic intermediates capable of binding to DNA. The relative rates of oxidative metabolism to electrophiles or their precursors were NNN > NNK > BaP > NNAL. Correlation studies indicated involvement of cytochrome P4502A6 in the 5′-hydroxylation of NNN and cytochrome P4503A4 in the α-methylene hydroxylation and pyridine-N-oxidation of NNK and NNAL. The results of this study provide the first data on the comparative metabolism of these important carcinogens in human hepatic microsomes.

Footnotes

  • Send reprint requests to: Dr. Stephen S. Hecht, University of Minnesota Cancer Center, Box 806 UMHC, 420 Delaware St. S. E., Minneapolis, MN 55455.

  • This study was supported by Grants CA-44377, CA-46535, CA-44353, and ES-00267 from the National Institutes of Health.

  • 1 Present address: University of Minnesota Cancer Center, Box 806-UMHC, 420 Delaware Street, S.E., Minneapolis, MN 55455.

  • Abbreviations used are::
    BaP
    benzo[a]pyrene
    NNK
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    NNN
    N′-nitrosonornicotine
    PAH
    polycyclic aromatic hydrocarbon
    NNAL
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
    BaP-7
    8-diol,trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene
    BaP-7
    8-diol-9,10-epoxide,trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene
    BaP-4
    5-diol,trans-4,5-dihydro-4,5-dihydroxybenzo[a]pyrene
    1-OH-BaP
    1-hydroxybenzo[a]pyrene
    3-OH-BaP
    3-hydroxybenzo[a]pyrene
    9-OH-BAP
    9-hydroxybenzo[a]pyrene
    NNK-N-oxide
    4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone
    NNAL-N-oxide
    4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanol
    keto aldehyde
    4-oxo-4-(3-pyridyl)butanal
    keto alcohol
    4-hydroxy-1-(3-pyridyl)-1-butanone
    lactol
    2-hydroxy-5-(3-pyridyl)tetrahydrofuran
    diol
    4-hydroxy-4-(3-pyridyl)-1-butanol
    keto acid
    4-oxo-4-(3-pyridyl)butyric acid
    hydroxy acid
    4-hydroxy-4-(3-pyridyl)butyric acid
    EROD
    ethoxyresorufin dealkylase
    MP (S)-mephenytoin-4′-hydroxylation
    BUF, bufuralol-1′-hydroxylation
    CZ
    chlorzoxazone-6-hydroxylation
    NF
    nifedipine oxidase
    COUM
    coumarin-7-hydroxylation
    • Received July 9, 1996.
    • Accepted October 31, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Comparative Metabolism of the Tobacco-Related Carcinogens Benzo[a]pyrene, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, andN′-Nitrosonornicotine in Human Hepatic Microsomes
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Research ArticleArticle

Comparative Metabolism of the Tobacco-Related Carcinogens Benzo[a]pyrene, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, andN′-Nitrosonornicotine in Human Hepatic Microsomes

Marianne E. Staretz, Sharon E. Murphy, Christopher J. Patten, Maria G. Nunes, Werner Koehl, Shantu Amin, Leeann A. Koenig, F. Peter Guengerich and Stephen S. Hecht
Drug Metabolism and Disposition February 1, 1997, 25 (2) 154-162;

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Research ArticleArticle

Comparative Metabolism of the Tobacco-Related Carcinogens Benzo[a]pyrene, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, andN′-Nitrosonornicotine in Human Hepatic Microsomes

Marianne E. Staretz, Sharon E. Murphy, Christopher J. Patten, Maria G. Nunes, Werner Koehl, Shantu Amin, Leeann A. Koenig, F. Peter Guengerich and Stephen S. Hecht
Drug Metabolism and Disposition February 1, 1997, 25 (2) 154-162;
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