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Research ArticleToxicology

Metabolism of [D10]Phenanthrene to Tetraols in Smokers for Potential Lung Cancer Susceptibility Assessment: Comparison of Oral and Inhalation Routes of Administration

Yan Zhong, Jing Wang, Steven G. Carmella, J. Bradley Hochalter, Diane Rauch, Andrew Oliver, Joni Jensen, Dorothy K. Hatsukami, Pramod Upadhyaya, Cheryl Zimmerman and Stephen S. Hecht
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 353-361; DOI: https://doi.org/10.1124/jpet.111.181719
Yan Zhong
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Jing Wang
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Steven G. Carmella
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J. Bradley Hochalter
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Diane Rauch
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Andrew Oliver
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Joni Jensen
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Dorothy K. Hatsukami
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Pramod Upadhyaya
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Cheryl Zimmerman
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Stephen S. Hecht
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Abstract

Polycyclic aromatic hydrocarbons (PAHs) are believed to be among the causative agents for lung cancer in smokers. PAHs require metabolic activation for carcinogenicity. One pathway produces diol epoxides that react with DNA, causing mutations. Because diol epoxides are converted to tetraols, quantitation of tetraols can potentially be used to identify smokers who may be at higher risk for lung cancer. Our approach uses [D10]phenanthrene, a labeled version of phenanthrene, a noncarcinogenic PAH structurally analogous to carcinogenic PAH. Although smokers are exposed to PAH by inhalation, oral dosing would be more practical for phenotyping studies. Therefore, we investigated [D10]phenanthrene metabolism in smokers after administration by inhalation in cigarette smoke or orally. Sixteen smokers received 10 μg of [D10]phenanthrene in a cigarette or orally. Plasma and urine samples were analyzed for [D10]r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene ([D10]PheT), the major end product of the diol epoxide pathway, by gas chromatography-negative ion chemical ionization-tandem mass spectrometry. The ratios of [D10]PheT (oral dosing/inhalation) in 15 smokers were 1.03 ± 0.32 and 1.02 ± 0.35, based on plasma area under the concentration-time curve (0-∞) and total 48-h urinary excretion, respectively. Overall, there was no significant difference in the extent of [D10]PheT formation after the two different routes of exposure in smokers. A large interindividual variation in [D10]PheT formation was observed. These results demonstrate that the level of [D10]PheT in urine after oral dosing of [D10]phenanthrene can be used to assess individual capacity of PAH metabolism by the diol epoxide pathway.

Footnotes

  • This study was supported by the National Institutes of Health National Cancer Institute [Grant CA-92025]. Biostatistical analysis was carried out by Ryan Shanley, Biostatistics and Informatics Shared Resource, Masonic Cancer Center, which is supported in part by the National Institutes of Health National Cancer Institute [Grant CA-77598].

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

    doi:10.1124/jpet.111.181719.

  • ABBREVIATIONS:

    PAH
    polycyclic aromatic hydrocarbon
    BaP
    benzo[a]pyrene
    Phe
    phenanthrene
    PheT
    r,1-t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene
    HOPhe
    hydroxyphenanthrene
    HOPhe-TMS
    HOPhe-tetratrimethylsilyl ether
    anti-PheDE-1-NAC
    N-acetyl-S-(r-4,t-2,3-trihydroxy-1,2,3,4-tetrahydro-c-1-phenanthryl)-l-cysteine
    GC
    gas chromatography
    MS/MS
    tandem mass spectrometry
    EI
    electron impact
    AUC
    area under the concentration-time curve
    CI
    confidence interval.

  • Received March 17, 2011.
  • Accepted April 21, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleToxicology

Metabolism of [D10]Phenanthrene to Tetraols in Smokers for Potential Lung Cancer Susceptibility Assessment: Comparison of Oral and Inhalation Routes of Administration

Yan Zhong, Jing Wang, Steven G. Carmella, J. Bradley Hochalter, Diane Rauch, Andrew Oliver, Joni Jensen, Dorothy K. Hatsukami, Pramod Upadhyaya, Cheryl Zimmerman and Stephen S. Hecht
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 353-361; DOI: https://doi.org/10.1124/jpet.111.181719

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Research ArticleToxicology

Metabolism of [D10]Phenanthrene to Tetraols in Smokers for Potential Lung Cancer Susceptibility Assessment: Comparison of Oral and Inhalation Routes of Administration

Yan Zhong, Jing Wang, Steven G. Carmella, J. Bradley Hochalter, Diane Rauch, Andrew Oliver, Joni Jensen, Dorothy K. Hatsukami, Pramod Upadhyaya, Cheryl Zimmerman and Stephen S. Hecht
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 353-361; DOI: https://doi.org/10.1124/jpet.111.181719
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