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Rapid CommunicationShort Communication

Preferential Glutathione Conjugation of a Reverse Diol Epoxide Compared with a Bay Region Diol Epoxide of Benzo[a]pyrene in Human Hepatocytes

Pramod Upadhyaya, J. Bradley Hochalter, Silvia Balbo, Edward J. McIntee and Stephen S. Hecht
Drug Metabolism and Disposition September 2010, 38 (9) 1397-1402; DOI: https://doi.org/10.1124/dmd.110.034181
Pramod Upadhyaya
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J. Bradley Hochalter
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Silvia Balbo
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Edward J. McIntee
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Stephen S. Hecht
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Abstract

Many studies have examined the relationship between polymorphisms in glutathione S-transferase genes and cancer in people exposed to polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene (BaP), but the results to date have been modest. Missing from these studies has been an exploration of the formation of the appropriate glutathione conjugates in humans. We incubated human hepatocytes from 10 donors with racemic anti-BaP-7,8-diol-9,10-epoxide (BPDE), believed to be a major ultimate carcinogen of BaP, or with the noncarcinogenic reverse diol epoxide, racemic anti-BaP-9,10-diol-7,8-epoxide (rev-BPDE). Incubations were carried out for 12 or 24 h. We used high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring at m/z 464 → m/z 317 to analyze the incubation mixtures for the mercapturic acid products that would result from glutathione conjugation. The standard mercapturic acids were synthesized by reaction of BPDE or rev-BPDE with N-acetylcysteine. We obtained convincing evidence in human hepatocytes for mercapturic acid formation from rev-BPDE in all 10 samples, in amounts up to 17 pmol/ml. However, we could detect mercapturic acids from BPDE in only 1 of 10 samples (0.05 pmol/ml). Taken together with our similar previous results of analyses of phenanthrene metabolites in human hepatocytes and human urine, the results of this study indicate that conjugation of BPDE with glutathione is a minor pathway in humans, indicating that glutathione S-transferase genotyping is not an effective method for assessing risk of PAH-induced cancer in humans, at least with respect to the diol epoxide pathway of PAH carcinogenesis.

Footnotes

  • This work was supported by the National Institutes of Health National Cancer Institute [Grant CA-92025].

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

    doi:10.1124/dmd.110.034181.

  • ABBREVIATIONS:

    PAH
    polycyclic aromatic hydrocarbons
    BaP
    benzo[a]pyrene
    BPDE
    anti-BaP-7,8-diol-9,10-epoxide
    GST
    glutathione S-transferase
    Phe
    phenanthrene
    Phe-1,2-D-3,4-E
    anti-Phe-1,2-diol-3,4-epoxide
    Phe-3,4-D-1,2-E
    anti-Phe-3,4-diol-1,2-epoxide
    Phe-1,2-D-4-NAC
    4-(N-acetylcysteinyl)-1,2,3-trihydroxy-1,2,3,4-tetrahydrophenanthrene
    Phe-3,4-D-1-NAC
    1-(N-acetylcysteinyl)-2,3,4-trihydroxy-1,2,3,4-tetrahydrophenanthrene rev-BPDE, anti-BaP-9,10-diol-7,8-epoxide
    Phe-9-hydroxy-10-NAC
    10-(N-acetylcysteinyl)-9-hydroxy-9,10-dihydrophenanthrene
    NAC
    N-acetylcysteine
    rev-BPDE-7-NAC
    7-(N-acetylcsyteinyl)-8,9,10-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene
    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    MS/MS
    tandem mass spectrometry
    ESI
    electrospray ionization
    BPDE-10-NAC
    10-(N-acetylcysteinyl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene
    CDNB
    1-chloro-2,4-dinitrobenzene
    LC-ESI-MS/MS-SRM
    liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring.

  • Received April 28, 2010.
  • Accepted June 14, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (9)
Drug Metabolism and Disposition
Vol. 38, Issue 9
1 Sep 2010
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Rapid CommunicationShort Communication

Preferential Glutathione Conjugation of a Reverse Diol Epoxide Compared with a Bay Region Diol Epoxide of Benzo[a]pyrene in Human Hepatocytes

Pramod Upadhyaya, J. Bradley Hochalter, Silvia Balbo, Edward J. McIntee and Stephen S. Hecht
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1397-1402; DOI: https://doi.org/10.1124/dmd.110.034181

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Rapid CommunicationShort Communication

Preferential Glutathione Conjugation of a Reverse Diol Epoxide Compared with a Bay Region Diol Epoxide of Benzo[a]pyrene in Human Hepatocytes

Pramod Upadhyaya, J. Bradley Hochalter, Silvia Balbo, Edward J. McIntee and Stephen S. Hecht
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1397-1402; DOI: https://doi.org/10.1124/dmd.110.034181
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