Dataset Information

Genetic variation in the bioactivation pathway for polycyclic hydrocarbons and heterocyclic amines in relation to risk of colorectal neoplasia.

ABSTRACT: Animal work implicates chemical carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs) as contributing to the development of colorectal cancer (CRC). The epidemiologic evidence, however, remains inconsistent possibly due to intra-individual variation in bioactivation of these compounds. We conducted a case-control study of colorectal adenoma (914 cases, 1185 controls) and CRC (496 cases, 607 controls) among Japanese Americans, European Americans and Native Hawaiians to investigate the association of genetic variation in the PAH and HAA bioactivation pathway (CYP1A1, CYP1A2, CYP1B1, AHR and ARNT) identified through sequencing with risk of colorectal neoplasia, as well as their interactions with smoking and intakes of red meat and HAAs. The A allele for ARNT rs12410394 was significantly inversely associated with CRC [odds ratios (ORs) and 95% confidence intervals (CIs) for GG, AG and AA genotypes: 1.00, 0.66 (0.48-0.89), 0.54 (0.37-0.78), P(trend) = 0.0008] after multiple comparison adjustment. CYP1A2 rs11072508 was marginally significantly associated with CRC, where each copy of the T allele was associated with reduced risk (OR: 0.72, 95% CI: 0.58-0.88, P(trend) = 0.0017). No heterogeneity of genetic effects across racial/ethnic groups was detected. In addition, no significant interaction was observed after adjusting for multiple testing between genetic variants and pack-years of smoking, intake of red meat or HAAs (PhIP, MeIQx, Di-MeIQx or total HAAs) or NAT2 genotype (Rapid versus Slow or Intermediate). This study suggests that the genomic region around ARNT rs12410394 may harbor variants associated with CRC.

SUBMITTER: Wang H

PROVIDER: S-EPMC3026844 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Genetic variation in the bioactivation pathway for polycyclic hydrocarbons and heterocyclic amines in relation to risk of colorectal neoplasia.

Wang Hansong H Yamamoto Jennifer F JF Caberto Christian C Saltzman Barbara B Decker Robert R Vogt Thomas M TM Yokochi Lance L Chanock Stephen S Wilkens Lynne R LR Le Marchand Loïc L

Carcinogenesis 20101116 2

Animal work implicates chemical carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs) as contributing to the development of colorectal cancer (CRC). The epidemiologic evidence, however, remains inconsistent possibly due to intra-individual variation in bioactivation of these compounds. We conducted a case-control study of colorectal adenoma (914 cases, 1185 controls) and CRC (496 cases, 607 controls) among Japanese Americans, European Americans and ...[more]

PMID: 21081473

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Project description:2-Amino-9H-pyrido[2,3-b]indole (A?C) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic heterocyclic aromatic amines (HAA) that arise during the burning of tobacco and cooking of meats. UDP-glucuronosyltransferases (UGT) detoxicate many procarcinogens and their metabolites. The genotoxic N-hydroxylated metabolite of A?C, 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-A?C), undergoes glucuronidation to form the isomeric glucuronide (Gluc) conjugates N(2)-(?-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (A?C-HON(2)-Gluc) and O-(?-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (A?C-HN(2)-O-Gluc). A?C-HON(2)-Gluc is a stable metabolite but A?C-HN(2)-O-Gluc is a biologically reactive intermediate, which covalently adducts to DNA at levels that are 20-fold higher than HONH-A?C. We measured the rates of formation of A?C-HON(2)-Gluc and A?C-HN(2)-O-Gluc in human organs: highest activity occurred with liver and kidney microsomes, and lesser activity was found with colon and rectum microsomes. A?C-HN(2)-O-Gluc formation was largely diminished in liver and kidney microsomes, by niflumic acid, a selective inhibitor UGT1A9. In contrast, A?C-HON(2)-Gluc formation was less affected and other UGT contribute to N(2)-glucuronidation of HONH-A?C. UGT were reported to catalyze the formation of isomeric Gluc conjugates at the N(2) and N3 atoms of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP), the genotoxic metabolite of PhIP. However, we found that the N3-Gluc of HONH-PhIP also covalently bound to DNA at higher levels than HONH-PhIP. The product ion spectra of this Gluc conjugate acquired by ion trap mass spectrometry revealed that the Gluc moiety was linked to the oxygen atom of HONH-PhIP and not the N3 imidazole atom of the oxime tautomer of HONH-PhIP as was originally proposed. UGT1A9, an abundant UGT isoform expressed in human liver and kidney, preferentially forms the O-linked Gluc conjugates of HONH-A?C and HONH-PhIP as opposed to their detoxicated N(2)-Gluc isomers. The regioselective O-glucuronidation of HONH-A?C and HONH-PhIP, by UGT1A9, is a mechanism of bioactivation of these ubiquitous HAAs.

Dataset Information

Genetic variation in the bioactivation pathway for polycyclic hydrocarbons and heterocyclic amines in relation to risk of colorectal neoplasia.

Publications

Genetic variation in the bioactivation pathway for polycyclic hydrocarbons and heterocyclic amines in relation to risk of colorectal neoplasia.

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