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Research ArticleArticle

Glucuronidation: An Important Mechanism for Detoxification of Benzo[a]Pyrene Metabolites in Aerodigestive Tract Tissues

Zhong Zheng, Jia-Long Fang and Philip Lazarus
Drug Metabolism and Disposition April 2002, 30 (4) 397-403; DOI: https://doi.org/10.1124/dmd.30.4.397
Zhong Zheng
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Jia-Long Fang
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Philip Lazarus
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Abstract

UDP-glucuronosyltransferases (UGTs) have been implicated as important detoxifying enzymes for several major tobacco carcinogens. Because the aerodigestive tract is a primary target for exposure to tobacco smoke carcinogens, the major goal of the present study was to determine whether aerodigestive tract tissues exhibit glucuronidating activity against metabolites of benzo[a]pyrene (BaP) and to explore the pattern of expression of UGT genes in a series of aerodigestive tract tissue specimens. Glucuronidation of the phenolic BaP metabolites 3-, 7-, and 9-hydroxy-BaP was observed in all upper aerodigestive tract tissue microsome specimens tested, as determined by high-pressure liquid chromatography analysis. Glucuronidating activity toward the procarcinogenic BaP metabolitetrans-BaP-7,8-dihydrodiol(±) was also detected in aerodigestive tract tissues. By semiquantitative duplex reverse transcription-polymerase chain reaction analysis, UGT1A7 and UGT1A10 were shown to be well expressed in all aerodigestive tract tissues examined, including tongue, tonsil, floor of mouth, larynx, and esophagus. UGT1A8 and UGT1A6 were expressed primarily in larynx; no expression was observed for UGTs 1A1, 1A3, 1A4, 1A5, 1A9. Of the family 2B UGTs, only UGT2B4 and UGT2B17 exhibited significant levels of expression in aerodigestive tract tissues. Of the aerodigestive tract-expressing UGTs, only UGTs 1A7, 1A8, and 1A10 exhibited glucuronidating activity against 7-hydroxy-BaP, with UGT1A10 exhibiting the highest affinity as determined by kinetic analysis (Km = 49 μM). No UGT expression or glucuronidating activity was observed for any of the lung specimens analyzed in this study. These results suggest that several family 1 UGTs may potentially play an important role in BaP detoxification in the aerodigestive tract.

Footnotes

  • ↵1 These authors contributed equally to this work.

  • These studies were supported by Public Health Service (PHS) Grants DE12206 and DE13158 (National Institute of Dental and Craniofacial Research) to P. Lazarus and PHS Grant CA68384 (National Cancer Institute; P. Lazarus, project leader; Steven Stellman, principal investigator).

  • Abbreviations used are::
    UGT
    UDP-glucuronosyltransferase
    NNK
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    BaP
    benzo[a]pyrene
    HPLC
    high-pressure liquid chromatography
    RT-PCR
    reverse transcription-polymerase chain reaction
    3-OH-BaP
    3-hydroxy-benzo[a]pyrene
    7-OH-BaP
    7-hydroxy-benzo[a]pyrene
    9-OH-BaP
    9-hydroxy-benzo[a]pyrene
    BaP-3-O-Gluc
    3-benzo[a]pyrenyl-β-d-glucopyranosiduronic acid
    BaP-7-O-Gluc
    7-benzo[a]pyrenyl-β-d-glucopyranosiduronic acid
    BaP-9-O-Gluc
    9-benzo[a]pyrenyl-β-d-glucopyranosiduronic acid
    • Received September 12, 2001.
    • Accepted December 18, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (4)
Drug Metabolism and Disposition
Vol. 30, Issue 4
1 Apr 2002
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Research ArticleArticle

Glucuronidation: An Important Mechanism for Detoxification of Benzo[a]Pyrene Metabolites in Aerodigestive Tract Tissues

Zhong Zheng, Jia-Long Fang and Philip Lazarus
Drug Metabolism and Disposition April 1, 2002, 30 (4) 397-403; DOI: https://doi.org/10.1124/dmd.30.4.397

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Research ArticleArticle

Glucuronidation: An Important Mechanism for Detoxification of Benzo[a]Pyrene Metabolites in Aerodigestive Tract Tissues

Zhong Zheng, Jia-Long Fang and Philip Lazarus
Drug Metabolism and Disposition April 1, 2002, 30 (4) 397-403; DOI: https://doi.org/10.1124/dmd.30.4.397
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