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

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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.

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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

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Acknowledgements

This work was supported in part by the COE Program in the 21st Century, the Global COE program and Grant-in-Aid for Scientific Research (19590070, 19590151) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. We gratefully acknowledge Shiho Taniguchi for excellent technical assistance.

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Authors and Affiliations

  1. Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan

    Junko Sugatani, Kousuke Mizushima, Makoto Osabe, Kasumi Yamakawa, Akira Ikari & Masao Miwa

  2. Global Center of Excellence for Innovation in Human Health Sciences, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Surugaku, Shizuoka, Shizuoka, 422-8526, Japan

    Junko Sugatani

  3. First Department of Internal Medicine, Gunma University Scgool of Medicine, Maebashi, Gunma, 371-8511, Japan

    Satoru Kakizaki, Hitoshi Takagi & Masatomo Mori

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  1. Junko Sugatani
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  2. Kousuke Mizushima
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  3. Makoto Osabe
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  4. Kasumi Yamakawa
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  9. Masao Miwa
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Correspondence to Masao Miwa.

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Sugatani, J., Mizushima, K., Osabe, M. et al. Transcriptional regulation of human UGT1A1 gene expression through distal and proximal promoter motifs: implication of defects in the UGT1A1 gene promoter. Naunyn-Schmied Arch Pharmacol 377, 597–605 (2008). https://doi.org/10.1007/s00210-007-0226-y

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