UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver.
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-N(2)-glucuronide (N(2)G), 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 N(2)G (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 N(2)G 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.
Girard
Hugo
H
Laboratory of Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, 2705 Boulevard Laurier, Québec G1V 4G2, Canada.
Thibaudeau
Jean
J
Court
Michael H
MH
Fortier
Louis-Charles
LC
Villeneuve
Lyne
L
Caron
Patrick
P
Hao
Qin
Q
von Moltke
Lisa L
LL
Greenblatt
David J
DJ
Guillemette
Chantal
C
D002273:Carcinogens / Q000378:metabolism*; D004032:Diet; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D000099148:UGT1A1 Enzyme
D002273:Carcinogens; D020719:Glucuronides; D014453:Glucuronosyltransferase; D007093:Imidazoles; D000099148:UGT1A1 Enzyme; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine