Transcriptional regulation of human UGT1A1 gene expression through distal and proximal promoter motifs: implication of defects in the UGT1A1 gene promoter
| Autor: | Makoto Osabe, Hitoshi Takagi, Masao Miwa, Akira Ikari, Satoru Kakizaki, Masatomo Mori, Junko Sugatani, Kasumi Yamakawa, Kousuke Mizushima |
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| Rok vydání: | 2008 |
| Předmět: |
Adult
Male Receptors Steroid Transcription Genetic Receptors Cytoplasmic and Nuclear digestive system Gene Expression Regulation Enzymologic Receptors Glucocorticoid Glucocorticoid receptor Constitutive androstane receptor Transcriptional regulation Humans Hepatocyte Nuclear Factor 1-alpha Glucuronosyltransferase Promoter Regions Genetic Enhancer Constitutive Androstane Receptor Aged Hyperbilirubinemia Pharmacology Regulation of gene expression Pregnane X receptor Polymorphism Genetic biology Activator (genetics) Pregnane X Receptor General Medicine Middle Aged Aryl hydrocarbon receptor Molecular biology Receptors Aryl Hydrocarbon biology.protein Female Transcription Factors |
| Zdroj: | Naunyn-Schmiedeberg's Archives of Pharmacology. 377:597-605 |
| ISSN: | 1432-1912 0028-1298 |
| DOI: | 10.1007/s00210-007-0226-y |
| Popis: | Human UDP-glucuronosyltransferase (UGT)1A1 is a critical enzyme responsible for detoxification and metabolism of endogenous and exogenous lipophilic compounds, such as potentially neurotoxic bilirubin and the anticancer drug irinotecan SN-38, via conjugation with glucuronic acid. A 290-bp distal enhancer module, phenobarbital-responsive enhancer module of UGT1A1 (gtPBREM), fully accounts for constitutive androstane receptor (CAR)-, pregnane X receptor (PXR)-, glucocorticoid receptor (GR)-, and aryl hydrocarbon receptor (AhR)-mediated activation of the UGT1A1 gene. This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. Moreover, we assessed the influence of the TA repeat polymorphism and gtPBREM T-3279G mutation on transcriptional activation of UGT1A1 by CAR, PXR, GR, and AhR. Transcriptional activation of the A(TA)(7)TAA mutant by CAR, the PXR activator rifampicin, the GR activator dexamethasone, and the AhR activator benzo[a]pyrene was more reduced than that of the T-3279G variant, and the activity of the UGT1A1 promoter with both T-3279G and A(TA)(7)TAA mutations was still lower. Thus, UGT1A1 gene promoter variations, including the TA repeat polymorphism and T-3279G gtPBREM, have important clinical implications. |
| Databáze: | OpenAIRE |
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