The regulation of the carcinogen detoxifying UDP-glucuronosyltransferase UGT1A7 by 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) is altered by a functional promoter variant

Introduction: The UGT-Glucuronosyltransferase (UGT) 1A7 plays an important role in the metabolism of endogenous and xenobiotic substrates, which include environmental carcinogens and drugs such as the chemotherapeutic compound irinotecan. Low activity alleles of UGT1A7 characterized by variations within the coding and non-coding sequence are associated with cancer predisposition and drug toxicity. The transcriptional regulation of this gene by xenobiotics and a putative influence of SNP variants not completely characterized. Aim of this study was therefore to analyze the regulation of UGT1A7 via TCDD and to elucidate the impact of a functional UGT1A7 promoter polymorphism (57T>G) on inducibility. Methods: Luciferase reporter gene constructs of the UGT1A7 5rsquor; non-coding promoter region were analyzed by induction experiments with TCDD in HepG2 and KYSE cells. A transcription factor binding motif was identified by site-directed mutagenesis. Results: Reporter gene assays showed 17.7-fold UGT1A7 inducibility by TCDD in HepG2 cells, which was significantly lower in the presence of the -57T>G promoter polymorphism (12.4-fold). Interestingly, UGT1A7 was not highly inducible (3-fold) in the esophageal cell line KYSE70. A DNA binding motif for the aryl hydrocarbon receptor (AhR), which mediates induction by TCDD, was identified. Mutagenesis of this element led to a significant reduction of inducibility. Conclusions: Inducibility of the carcinogen-detoxifying UGT1A7 by xenobiotics has not been reported to date. This study the first time demonstrates AhR-mediated induction of the human UGT1A7, which is downregulated in the presence of the -57T>G promoter polymorphism (UGT1A7*12, present in 38% of the population). Genotype dependent reduced induction may Influence drug toxicity and cancer disposition associated with the low-activity UGT1A7*3 coding region risk alleles, which are linked to the -57T>G variant.

AhR - TCDD - UDP-Glucuronosyltransferasen - UGT1A7