Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 377, Issue 4, pp 597–605

Transcriptional regulation of human UGT1A1 gene expression through distal and proximal promoter motifs: implication of defects in the UGT1A1 gene promoter

  • Junko Sugatani
  • Kousuke Mizushima
  • Makoto Osabe
  • Kasumi Yamakawa
  • Satoru Kakizaki
  • Hitoshi Takagi
  • Masatomo Mori
  • Akira Ikari
  • Masao Miwa
Original Article

DOI: 10.1007/s00210-007-0226-y

Cite this article as:
Sugatani, J., Mizushima, K., Osabe, M. et al. Naunyn-Schmied Arch Pharmacol (2008) 377: 597. doi:10.1007/s00210-007-0226-y

Abstract

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 1α (HNF1α) 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)7TAA 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)7TAA mutations was still lower. Thus, UGT1A1 gene promoter variations, including the TA repeat polymorphism and T-3279G gtPBREM, have important clinical implications.

Keywords

UGT1A1 Transcriptional regulation HNF1α Polymorphism gtPBREM variant TA repeat polymorphism 

Abbreviations

AhR

aryl hydrocarbon receptor

CAR

constitutive androstane receptor

P450

cytochrome P450

GR

glucocorticoid receptor

gtPBREM

phenobarbital-responsive enhancer module of UGT1A1

HNF1α

hepatocyte nuclear factor 1α

PCR

polymerase chain reaction

pGL3-tk

pGL3-tk-firefly luciferase vector

PXR

pregnane X receptor

RXR

retinoid X receptor

Tk

thymidine kinase promoter

UGT

UDP-glucuronosyltransferase

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Junko Sugatani
    • 1
    • 2
  • Kousuke Mizushima
    • 1
  • Makoto Osabe
    • 1
  • Kasumi Yamakawa
    • 1
  • Satoru Kakizaki
    • 3
  • Hitoshi Takagi
    • 3
  • Masatomo Mori
    • 3
  • Akira Ikari
    • 1
  • Masao Miwa
    • 1
  1. 1.Department of Pharmaco-BiochemistrySchool of Pharmaceutical Sciences, University of ShizuokaShizuokaJapan
  2. 2.Global Center of Excellence for Innovation in Human Health SciencesSchool of Pharmaceutical Sciences, University of ShizuokaShizuokaJapan
  3. 3.First Department of Internal MedicineGunma University Scgool of MedicineMaebashi, GunmaJapan

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