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Mol Pharmacol. 2018 Mar 8. pii: mol.117.110619. doi: 10.1124/mol.117.110619. [Epub ahead of print]

Cooperative regulation of intestinal UDP-glucuronosyltransferases by CDX2 and HNF4α is mediated by a novel composite regulatory element.

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Flinders University.
Flinders University School of Medicine.
Flinders University;


The UDP-glucuronosyltransferases (UGTs) of the gastrointestinal tract (GIT) have a crucial role in protection against dietary toxins and metabolism of orally administered drugs. A subset of UGTs including UGT1A8, UGT1A9, and UGT1A10 are highly expressed in GI tissues and this has been shown to be at least partly directed by the caudal homeodomain transcription factor, CDX2. We sought to further define the factors involved in regulation of the UGT1A8-1A10 genes and identified a novel composite element located within the proximal promoters of these three genes that binds to both CDX2 and the hepatocyte nuclear factor HNF4α, and mediates synergistic activation by these factors. We also show that HNF4α and CDX2 are required for the expression of these UGT genes in colon cancer cell lines, and show robust correlation of UGT expression with CDX2 and HNF4α levels in normal human colon. Finally we reveal that these factors are involved in the differential expression pattern of UGT1A8 and UGT1A10, which are intestinal-specific, and that of UGT1A9, which is expressed in both intestine and liver. These studies lead to a model for the developmental patterning of UGT1A8, UGT1A9, and UGT1A10 in hepatic and/or extrahepatic tissues involving discrete regulatory modules that can function (independently and cooperatively) in a context-dependent manner.


Drug metabolism; First-pass metabolism; Gene regulation; Glucuronidation; Transcription factors; Transcriptional regulation; UDP glucuronosyltransferase (UGT)

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