Regulation and function of family 1 and family 2 UDP-glucuronosyltransferase genes (UGT1A, UGT2B) in human oesophagus

Abstract

Human UDP-glucuronosyltransferases (UGTs) are expressed in a tissue-specific fashion in hepatic and extrahepatic tissues [Strassburg, Manns and Tukey (1998) J. Biol. Chem. 273, 8719-8726]. Previous work suggests that these enzymes play a protective role in chemical carcinogenesis [Strassburg, Manns and Tukey (1997) Cancer Res. 57, 2979-2985]. In this study, UGT1 and UGT2 gene expression was investigated in human oesophageal epithelium and squamous-cell carcinoma in addition to the characterization of individual UGT isoforms using recombinant protein. UGT mRNA expression was characterized by duplex reverse transcriptase-PCR analysis and revealed the expression of UGT1A7, UGT1A8, UGT1A9 and UGT1A10 mRNAs. UGT1A1, UGT1A3, UGT1A4, UGT1A5 and UGT1A6 transcripts were not detected. UGT2 expression included UGT2B7, UGT2B10 and UGT2B15, but UGT2B4 mRNA was absent. UGT2 mRNA was present at significantly lower levels than UGT1 transcripts. This observation was in agreement with the analysis of catalytic activities in oesophageal microsomal protein, which was characterized by high glucuronidation rates for phenolic xenobiotics, all of which are classical UGT1 substrates. Whereas UGT1A9 was not regulated, differential regulation of UGT1A7 and UGT1A10 mRNA was observed between normal oesophageal epithelium and squamous-cell carcinoma. Expression and analysis in vitro of recombinant UGT1A7, UGT1A9, UGT1A10, UGT2B7 and UGT2B15 demonstrated that UGT1A7, UGT1A9 and UGT1A10 catalysed the glucuronidation of 7-hydroxybenzo(alpha)pyrene, as well as other environmental carcinogens, such as 2-hydroxyamino-1-methyl-6-phenylimidazo-(4, 5-beta)-pyridine. Although UGT1A9 was not regulated in the carcinoma tissue, the five-fold reduction in 7-hydroxybenzo(alpha)pyrene glucuronidation could be attributed to regulation of UGT1A7 and UGT1A10. These data elucidate an individual regulation of human UGT1A and UGT2B genes in human oesophagus and provide evidence for specific catalytic activities of individual human UGT isoforms towards environmental carcinogens that have been implicated in cellular carcinogenesis.

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

“…UGT1A7 has been implicated in the glucuronidation of carcinogenic metabolites of tobacco-specific nitrosamines 138,139 and BaP. 65,140 The expression pattern of UGT1A7 is also consistent with a role in the protection against these chemicals.…”

“…65,140 The expression pattern of UGT1A7 is also consistent with a role in the protection against these chemicals. UGT1A7 is expressed in extrahepatic tissues with high levels in the stomach and the esophagus, 68,138 as well as in other tissues of the aerodigestive tract including the tongue, tonsil, floor of the mouth and larynx. 68,141 Owing to the expression pattern of UGT1A7 and its contribution in carcinogen detoxification, the potential role of UGT1A7 in the risk of developing tobacco-related cancers, Pharmacogenomics of human UGT enzymes C Guillemette more specifically orolaryngeal cancer, was recently explored.…”

“…The UGT2B7 protein is also found in the brain, kidney, pancreas, mammary gland, lung and gastrointestinal tract, and several additional tissues. 80,134,138,[144][145][146] A cytosine to thymine polymorphism at base pair 802, leading to a histidine (H) 268 to tyrosine (Y) amino-acid substitution (UGT2B7*2), has been identified. 147,148 Data from large genotyping studies suggest that approximately one-third of the Caucasian population expresses the variant UGT2B7*2/*2 genotype (Table 5).…”

Increased UGT1A3 and UGT1A7 Expression is Associated with Pancreatic Cancer

“…The UGT1A7 gene is differentially expressed in the human lung (Guillemette et al, 2000), esophagus (Strassburg et al, 1999a), stomach (Strassburg et al, 1997), small intestine and colon (Strassburg et al, 1998b;Strassburg et al, 1999b) but is absent from the liver (Strassburg et al, 2001). Ockenga et al (2003) reported high levels of UGT1A7 mRNA and low levels of UGT1A3 transcripts in normal pancreatic tissue.…”

“…An important superfamily of proteins that play a role in cellular detoxification and defense are the UDPglucuronosyltransferase, which are expressed in different tissues with xenobiotic contact and have been implicated in chemical carcinogenesis (Strassburg et al, 1999a). Human UGT1A genes are regulated in a tissue-spesific fashion in hepatic and extrahepatic tissues (Strassburg et al, 1998a).…”