Dataset Information

Genetic polymorphisms in human UDP-glucuronosyltransferases 1A7 and the risk of gastrointestinal carcinomas: A systematic review and network meta-analysis.

ABSTRACT: To identify the association between gastrointestinal carcinomas (GIC) risk and UDP-glucuronosyltransferases (UGTs) 1A7 polymorphisms through a systematic review and network meta-analysis.Seventeen studies were eligible, which included 7738 patients and 18 analyses. First, it was found that compared with non-cancer participants, UGT1A7*1 were significantly decreased in cancer patient groups, especially in hepatocellular carcinoma, colorectal carcinoma, and Asian population groups; UGT1A7*2 was significantly increased in hepatocellular carcinoma and Asian population groups; and UGT1A7*3 was significantly increased in hepatocellular carcinoma, colorectal carcinoma, Caucasian, and Asian population groups. Second, the UGT1A7 polymorphism alleles contrast model and the categorized UGT 1A7 genotypes were compared, and the outcomes revealed that the ratio of UGT1A7*3 vs *2 increased, which may indicate an increased risk for cancer, especially for the pancreatic carcinoma and Caucasian groups. The ratio of Intermediate vs Low increased as well, which may also indicate an increased risk for GIC.PubMed, Embase, and the Cochrane library were searched for publications up until May 2017. First, the UGT 1A7 gene polymorphisms genotype in GIC patients were compared with a non-cancer control group, and second, the UGT1A7 polymorphism alleles contrast model and UGT 1A7 genotypes categorized according to enzymatic activity were examined.There is a cancer risk associated with increased UGT1A7 *2 for the hepatocellular carcinoma and Asian groups and with increased UGT1A7 *3 for the hepatocellular carcinoma, colorectal carcinoma, Caucasian, and Asian groups. Moreover, in Caucasian patients with GIC, the ratio of UGT1A7 *3 vs *2 was increased.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5630419 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Genetic polymorphisms in human UDP-glucuronosyltransferases 1A7 and the risk of gastrointestinal carcinomas: A systematic review and network meta-analysis.

Zhang Yingshi Y Hou Jun J Feng Fan F Li Dandan D Jiang Qiyu Q Li Xiaojuan X Zhao Qingchun Q Li Bo-An BA

Oncotarget 20170627 39

<h4>Objective</h4>To identify the association between gastrointestinal carcinomas (GIC) risk and UDP-glucuronosyltransferases (UGTs) 1A7 polymorphisms through a systematic review and network meta-analysis.<h4>Results</h4>Seventeen studies were eligible, which included 7738 patients and 18 analyses. First, it was found that compared with non-cancer participants, UGT1A7*1 were significantly decreased in cancer patient groups, especially in hepatocellular carcinoma, colorectal carcinoma, and Asian ...[more]

PMID: 29029519

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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 polymorphisms in human UDP-glucuronosyltransferases 1A7 and the risk of gastrointestinal carcinomas: A systematic review and network meta-analysis.

Publications

Genetic polymorphisms in human UDP-glucuronosyltransferases 1A7 and the risk of gastrointestinal carcinomas: A systematic review and network meta-analysis.

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