Review
Regulation of UDP glucuronosyltransferases in the gastrointestinal tract

https://doi.org/10.1016/j.taap.2004.01.008Get rights and content

Abstract

The UDP glucuronosyltransferases (UGT) of the gastrointestinal (GI) tract have a crucial role in protection against the toxic effects of lipophilic chemicals in the environment. UGTs such as UGT1A7, UGT1A8, and UGT1A10 are exclusively expressed in gastrointestinal tissues, each with a unique tissue distribution pattern that is subject to interindividual variation. The factors regulating this tissue-specific expression and that contribute to variability are beginning to be elucidated. Studies on the UGT1A7, 1A8, 1A9, and 1A10 gene promoters in Caco-2 cells, an in vitro model of enterocytes of the gastrointestinal tract, have identified the caudal homeodomain transcription factor, Cdx2, as an important regulator of the UGT1A8 and 1A10 gene proximal promoters. This transcription factor is found exclusively in the small intestine and colon: it is absent in the gastric epithelium and the esophagus. Cdx2 regulates the UGT1A8 and 1A10 promoters in cooperation with hepatocyte nuclear factor 1α (HNF1α). It is noteworthy that UGT1A7 is not expressed in gastrointestinal tissue distal to the gastric mucosa and does not contain a Cdx2 binding site in its proximal promoter. Transcription factors, including Sp1, which differentially bind to the initiator regions of the UGT1A8, 1A9, and 1A10 promoters, also contribute to the differences in expression of these UGTs in Caco-2 cells. The identification of important regulatory regions of UGT genes expressed in the gastrointestinal tract, and the transcription factors that bind to these regions, will aid in the elucidation of factors that contribute to interindividual differences in gastrointestinal UGT expression. In turn, this will lead to further understanding of interindividual variation in the capacity of the GI tract to metabolize lipophilic chemicals and to act as a barrier to dietary toxins and orally administered drugs.

Section snippets

Glucuronidation in the gastrointestinal tract

One of the many pioneering aspects of Ed Bresnick's research was his studies on the regulation of cytochrome P450 (CYP) genes by xenobiotics. We have shared his interest in gene regulation, as many of the mechanisms that regulate CYP genes also operate on UDP glucuronosyltransferase (UGT) genes, although there are also important differences in regulation between the two gene families. In this review, we describe some of the factors that regulate UGTs of the gastrointestinal tract. The

UDP glucuronosyltransferases in the gastrointestinal tract

The UGT enzymes are members of a superfamily comprising four families in mammals (http://som.flinders.edu.au/FUSA/ClinPharm/UGT/). Only family 1 (UGT1) and family 2 (UGT2) use UDP glucuronic acid as sugar donor. Members of each family share more than 50% sequence identity with each other and less than 50% identity with members of the other family (Mackenzie et al., 1997). The nine members of family 1 are encoded from one gene locus. Two human liver ‘bilirubin’ UGT cDNAs were first isolated by

The Caco-2 cell as a model of the GI tract enterocyte

The human colonic adenocarcinoma cell line, Caco-2, is the most widely used enterocyte model for the study of gene expression in the GI tract. It is a transformed colon cell line, which displays virtually all characteristics of small intestinal villus enterocytes, that is, it forms a fully functional brush border and shows a large number of characteristics of absorptive enterocytes (Van Beers et al., 1995, and references therein). Caco-2 cells also express lactase and sucrase-isomaltase, two

Conclusions and future work

UGT1A7, UGT1A8, and UGT1A10 are exclusively expressed in the GI tract but their tissue distribution within this organ varies significantly. As described above, the mechanisms that regulate the GI expression of UGT genes are only just beginning to be elucidated. UGT1A7 expression appears to be limited to the upper GI tract, and in particular the stomach (Table 1). The lack of UGT1A7 expression in the lower GI tract may result from the absence of a functional Cdx2 binding site in its promoter.

Acknowledgements

This work was supported by grants from the Cancer Council of South Australia and the National Health and Medical Research Council of Australia. P.I.M. is a National Health and Medical Research Council Senior Principal Research Fellow.

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