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UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver
Author(s) -
Girard Hugo,
Thibaudeau Jean,
Court Michael H.,
Fortier LouisCharles,
Villeneuve Lyne,
Caron Patrick,
Hao Qin,
von Moltke Lisa L.,
Greenblatt David J.,
Guillemette Chantal
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20770
Subject(s) - glucuronidation , carcinogen , metabolite , chemistry , glucuronide , heterocyclic amine , metabolism , glucuronosyltransferase , bilirubin , mutagen , cytochrome p450 , enzyme , biochemistry , medicine , endocrinology , microsome , biology
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. (H EPATOLOGY 2005.)