ReviewRegulation of UDP glucuronosyltransferases in the gastrointestinal tract
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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2023, Toxicology and Applied PharmacologyEvaluation of inhibitors of intestinal UDP-glucuronosyltransferases 1A8 and 1A10 using raloxifene as a substrate in Caco-2 cells: Studies with four flavonoids of Scutellaria baicalensis
2021, Toxicology in VitroCitation Excerpt :UGT1A8 expression is observed predominantly in the lower gastrointestinal tract. UGT1A10 is expressed throughout the tract and, additionally, in the bile ducts (Gregory et al., 2004). These expression patterns suggests that UGT1A8 and UGT1A10 may play an important role in the metabolism of dietary xenobiotics (Mojarrabi and Mackenzie, 1998; Wang et al., 2016).
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2017, Pharmacological ResearchCitation Excerpt :UGT1A7, UGT1A8 and UGT1A10 are almost exclusively expressed in gastrointestinal tissues; UGT1A7 in the stomach and upper gastrointestinal tract and UGT1A8 and 1A10 in the small intestine and colon. The Caudal Homeodomain Transcription Factor, Cdx2, which is found exclusively in the small intestine and colon, is an important regulator of the UGT1A8 and 1A10 gene proximal promoters, in conjunction with hepatocyte Nuclear Factor 1α [69]. UGT1A7 which is not expressed in the small intestine and colon, does not contain a Cdx2 binding site in its proximal promoter.
1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10
2016, Translational ResearchCitation Excerpt :The human UGTs consists of 4 families, UGT1, UGT2A and 2B, UGT3, and UGT8, of which, UGT1, UGT2A and UGT2B are primarily involved in drug metabolism and are encoded by genes located on chromosome 2 and 4, respectively.15-17 Variability in UGT activity has been significantly associated with inter-individual differences in metabolism of a broad array of endogenous and exogenous compounds including many therapeutic agents.18 Previous studies have revealed that glucuronidation of MPA mainly involves UGT1A8 and UGT1A9, with UGT1A10 and UGT2B7 playing a minor role.10-14
Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases
2016, Food and Chemical ToxicologyCitation Excerpt :To date, at least twenty-two human UGTs have been identified, and they are classified into three subfamilies, namely UGT1A, UGT2A, and UGT2B, based on their amino acid sequence (Rowland et al., 2013). Most UGTs are expressed in the liver, but some isoforms, such as UGT1A7, UGT1A8, and UGT1A10, are expressed predominantly in the gastrointestinal tract (Gregory et al., 2004). Human intestinal UGTs are considered as important determinants in intestinal metabolism, especially for those oral phenolic compounds, such as flavonoids and courmarins (Zhang et al., 2007; Wu et al., 2011; Xia et al., 2015).