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Research ArticleArticle

UDP-Glucuronosyltransferase 1A10: Activity against the Tobacco-Specific Nitrosamine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, and a Potential Role for a Novel UGT1A10 Promoter Deletion Polymorphism in Cancer Susceptibility

Rene M. Balliet, Gang Chen, Ryan W. Dellinger and Philip Lazarus
Drug Metabolism and Disposition March 2010, 38 (3) 484-490; DOI: https://doi.org/10.1124/dmd.109.030569
Rene M. Balliet
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Gang Chen
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Ryan W. Dellinger
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Philip Lazarus
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Abstract

The extrahepatic UDP-glucuronosyltransferase 1A10 (UGT1A10) is a phase II metabolizing enzyme that is active against a number of potent carcinogens. In the present study, UGT1A10 was examined for activity against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the major procarcinogenic metabolite of the potent tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and the promoter region of UGT1A10 was examined for variants that could lead to altered UGT1A10 expression. UGT1A10-overexpressing cell homogenates exhibited high O-glucuronidation activity against NNAL (KM = 5.95 mM). A 2000-base pair (bp) product corresponding to the UGT1A10 proximal promoter region was polymerase chain reaction (PCR)-amplified using genomic DNA from 97 white subjects, and 42 of these were sequenced. In addition to a previously reported C/G single-nucleotide polymorphism at −1271 bp (rs2741032), a novel 1664-bp deletion located between nucleotides −190 to −1856 relative to the UGT1A10 translation start site was identified. Using real-time multiplex PCR, this deletion exhibited a prevalence of 0.022 in whites (n = 156) and 0.056 in blacks (n = 133). To determine whether either polymorphism altered gene expression, in vitro assays were performed using luciferase constructs containing up to 2000 bp of the proximal UGT1A10 promoter. Constructs containing the 1664-bp deletion exhibited a significant (p = 0.009) 3-fold increase in luciferase activity compared with constructs containing the wild-type UGT1A10 promoter. No effect on luciferase activity was observed for the UGT1A10−1271G promoter variant. These data are consistent with previous studies that indicate the presence of a transcriptional repressor element within the newly identified deletion and that this deletion polymorphism may contribute to altered UGT1A10 expression and altered carcinogen detoxification between individuals.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Dental and Craniofacial Research [Grant R01-DE13158]; the National Institutes of Health National Cancer Institute [Grant P01-CA68384]; and Pennsylvania Department of Health's Health Research Formula Funding Program [Grants 4100038714, 4100038715].

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

    doi:10.1124/dmd.109.030569.

  • ABBREVIATIONS:

    UGT
    UDP-glucuronosyltransferase
    NNK
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    PAH
    polycyclic aromatic hydrocarbons
    B[a]P
    benzo[a]pyrene
    PhIP
    2-amino-1-methyl-6-phenylimidazo[4,5-f]pyridine
    SNP
    single-nucleotide polymorphism
    NNAL
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
    UDPGA
    UDP-glucuronic acid
    HPLC
    high-pressure liquid chromatography
    MEM
    minimal essential medium
    bp
    base pair
    PCR
    polymerase chain reaction
    UTR
    untranslated region.

    • Received September 30, 2009.
    • Accepted December 8, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (3)
Drug Metabolism and Disposition
Vol. 38, Issue 3
1 Mar 2010
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UDP-Glucuronosyltransferase 1A10: Activity against the Tobacco-Specific Nitrosamine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, and a Potential Role for a Novel UGT1A10 Promoter Deletion Polymorphism in Cancer Susceptibility
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Research ArticleArticle

UDP-Glucuronosyltransferase 1A10: Activity against the Tobacco-Specific Nitrosamine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, and a Potential Role for a Novel UGT1A10 Promoter Deletion Polymorphism in Cancer Susceptibility

Rene M. Balliet, Gang Chen, Ryan W. Dellinger and Philip Lazarus
Drug Metabolism and Disposition March 1, 2010, 38 (3) 484-490; DOI: https://doi.org/10.1124/dmd.109.030569

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Research ArticleArticle

UDP-Glucuronosyltransferase 1A10: Activity against the Tobacco-Specific Nitrosamine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, and a Potential Role for a Novel UGT1A10 Promoter Deletion Polymorphism in Cancer Susceptibility

Rene M. Balliet, Gang Chen, Ryan W. Dellinger and Philip Lazarus
Drug Metabolism and Disposition March 1, 2010, 38 (3) 484-490; DOI: https://doi.org/10.1124/dmd.109.030569
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