Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

Abstract

The uridine diphosphoglucuronosyltransferases (UGTs) belong to a superfamily of enzymes that catalyse the glucuronidation of numerous endobiotics and xenobiotics. Several human hepatic and extrahepatic UGT isozymes have been characterized with respect to their substrate specificity, tissue expression and gene structure. Genetic polymorphisms have been identified for almost all the UGT family members. A wide variety of anticancer drugs, dietary chemopreventives and carcinogens are known to be conjugated by members of both UGT1A and UGT2B subfamilies. This review examines in detail each UGT isozyme known to be associated with cancer and carcinogenesis. The cancer-related substrates for several UGTs are summarized, and the functionally relevant genetic polymorphisms of UGTs are reviewed. A number of genotype-phenotype association studies have been carried out to characterize the role of UGT pharmacogenetics in several types of cancer, and these examples are discussed here. In summary, this review focuses on the role of the human UGT genetic polymorphisms in carcinogenesis, chemoprevention and cancer risk.

Alternative-splicing forms of the major phase II conjugating UGT1A gene negatively regulate glucuronidation in human carcinoma cell lines

“…ulaval.ca). 4,5 Until recently, no evidence of alternative splicing in the region of common exons (exons 2-5) has been shown for the UGT1A gene complex (GenBank AF297093). However, following the isolation of an UGT1A cDNA lacking C-term region from human kidney, the entire locus was screened for additional exons and a new alternative exon was uncovered between the coding exons 4 and 5, named exon 5b.…”

Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations

“…So far, 3 nonsynonymous single nucleotide polymorphisms (SNPs) (8G>A [C3Y], 98T>C [M33T], and 766G>A [D256N]) and a SNP at 726T>G resulting in a premature termination codon TAG (Y242X) have been reported in exon-1 of this gene (http://galien.pha.ulaval.ca/labocg/alleles/UGT1A/UGT1A9.htm). Among these SNPs, C3Y is located in the signal peptide of UGT1A9 protein, which is cleaved when the protein is integrated into the endoplasmic reticulum membrane [2,14]. Using HEK293 cells expressing UGT allelic variants, this polymorphism was not found to alter glucuronidation activity for anticancer drugs [14].…”

“…UDP-glucuronosyltransferases transfer the glucuronic acid moiety of UDPglucuronic acid to the substrate, thereby increasing the polarity of the substrate and facilitating its excretion in bile or urine [1,2]. Although glucuronidation is generally considered to be a detoxification mechanism, active and/or toxic glucuronide-conjugated metabolites are known to occur [3].…”

Association between Polymorphisms in UDP-glucuronosyltransferase 1A6 and 1A7 and Colorectal Cancer Risk

“…Genetic susceptibility to this disease may result from inherited mutations in genes involved in carcinogen metabolism and DNA repair (Paz-Elizur et al, 2008;Joshi et al, 2009;Zhao et al, 2012). Uridine diphosphate-glucuronosyltransferases (UGTs) play an important role in glucuronidation of various endogenous and exogenous compounds such as bilirubin, steroid hormones, bile acids, anticancer drugs, including heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) (Ciotti et al, 1997;van der Logt et al, 2004;Nagar et al, 2006). UGTs are on their structural and sequence homology (Jin et al, 1993).…”

“…UGTs are on their structural and sequence homology (Jin et al, 1993). The locus codes of nine functional proteins of the UGT1A family differ only in their N-terminus as a result of alternate splicing of independent exon 1 regions to a shared C-terminus encoded by exons 2 to 5 (Nagar et al, 2006).UGT1A6 is expressed in several human tissues, and catalyses the glucuronidation of small planar phenols and primary aromatic amines (Nagar et al 2006). Two functionally important SNPs arise in exon 1 of the gene, which result in T181A and R184S amino acid changes ( ), although alleles carrying only the T181A polymorphism ( ) or the R184S polymorphism ( ) have been described (http://www.pharmacogenomics.pha.ulaval.ca/files/ content/sites/pharmacogenomics/files/Nomenclature/ UGT1A/UGT1A6.htm).…”