Regulation of UDP glucuronosyltransferases in the gastrointestinal tract.
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 1alpha (HNF1alpha). 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.
Gregory
Philip A
PA
Department of Clinical Pharmacology, Flinders Medical Centre, Flinders University School of Medicine, Bedford Park, South Australia, 5042.
Lewinsky
Rikke H
RH
Gardner-Stephen
Dione A
DA
Mackenzie
Peter I
PI
D000818:Animals; D004064:Digestive System / Q000201:enzymology* / Q000378:metabolism; D020895:Enterocytes / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans
D020719:Glucuronides; D014453:Glucuronosyltransferase