UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver

Authors

  • Hugo Girard,

    1. Canada Research Chair in Pharmacogenomics, Laboratory of Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, Québec, Canada
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  • Jean Thibaudeau,

    1. Canada Research Chair in Pharmacogenomics, Laboratory of Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, Québec, Canada
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  • Michael H. Court,

    1. Department of Pharmacology and Experimental Therapeutics, Tufts University, Boston, MA
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  • Louis-Charles Fortier,

    1. Canada Research Chair in Pharmacogenomics, Laboratory of Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, Québec, Canada
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  • Lyne Villeneuve,

    1. Canada Research Chair in Pharmacogenomics, Laboratory of Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, Québec, Canada
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  • Patrick Caron,

    1. Canada Research Chair in Pharmacogenomics, Laboratory of Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, Québec, Canada
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  • Qin Hao,

    1. Department of Pharmacology and Experimental Therapeutics, Tufts University, Boston, MA
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  • Lisa L. von Moltke,

    1. Department of Pharmacology and Experimental Therapeutics, Tufts University, Boston, MA
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  • David J. Greenblatt,

    1. Department of Pharmacology and Experimental Therapeutics, Tufts University, Boston, MA
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  • Chantal Guillemette

    Corresponding author
    1. Canada Research Chair in Pharmacogenomics, Laboratory of Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, Québec, Canada
    • Canada Research Chair in Pharmacogenomics, Laboratory of Pharmacogenomics, CHUL Research Center, T3-48, 2705 Boul. Laurier, Québec, Canada, G1V 4G2
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    • fax: 418-654-2761


  • Potential conflict of interest: Nothing to report.

  • Preliminary data from this study were presented at the 2004 International Society for Study of Xenobiotics; Vancouver, Canada; August 29–September 2, 2004 and at the 11th Workshop on Glucuronidation, Dundee, Scotland; September 5–September 8, 2004.

Abstract

PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-f]pyridine), the most abundant heterocyclic amine in diet, is involved in the etiology of cancer. PhIP and its carcinogenic metabolite N-hydroxy-PhIP (N-OH-PhIP) are extensively conjugated by UDP-glucuronosyltransferase (UGTs) with wide variability. This study aimed to determine the genetic influence of UGTs on the hepatic detoxification of this carcinogen. The formation of N-OH-PhIP glucuronides was studied in 48 human liver samples by mass spectrometry. Liver samples were genotyped for common polymorphisms and correlated with UGT protein levels and N-OH-PhIP glucuronidation activities. The formation of four different N-OH-PhIP glucuronide metabolites was observed in all livers. The major metabolite was N-OH-PhIP-N2-glucuronide (N2G), which is the primary metabolite found in human urine, and showed a high interindividual variability (up to 28-fold). Using an heterologous expression system, the bilirubin-conjugating UGT1A1 enzyme was identified among all known UGTs (n = 16) as the predominant enzyme involved. The significant correlation between UGT1A1 protein content and formation of N2G (Rs = 0.87; P < .0001) suggests a critical role for UGT1A1 in the hepatic metabolism of this carcinogen. UGT1A1 expression was strongly determined by the presence of the common promoter polymorphisms, UGT1A1*28 (TATA box polymorphism) (P = .0031), −3156G/A (P = .0006) and −3279G/T (P = .0017), and rates of N2G were indeed correlated with these polymorphisms (P < .05), whether analyzed individually or in combination (haplotypes). In conclusion, UGT1A1 polymorphisms modulate the hepatic metabolism of the carcinogenic intermediate of PhIP and may determine the level of its exposure and potentially influence the risk of cancer through dietary exposure to HCAs. (HEPATOLOGY 2005.)

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