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.
Similar content being viewed by others
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
References
Akiyama TE, Ward JM, Gonzalez FJ (2000) Regulation of the liver fatty acid-binding protein gene by hepatocyte nuclear factor 1alpha (HNF1alpha). Alteration in fatty acid homeostasis in HNF1alpha-deficient mice. J Biol Chem 275:27117–27122
Aono S, Yamada Y, Keino H, Sasaoka Y, Nakagawa T, Onishi S, Mimura S, Koiwai O, Sato H (1994) A new type of defect in the gene for bilirubin uridine 5′-diphosphate-glucuronosyltransferase in a patient with Crigler-Najjar syndrome type I. Pediatr Res 35:629–632
Aono S, Adachi Y, Uyama E, Yamada Y, Keino H, Nanno T, Koiwai O, Sato H (1995) Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert’s syndrome. Lancet 345:958–959
Arabi Y, Morgan BJ, Goodman B, Puleo DS, Xie A, Skatrud JB (1999) Daytime blood pressure elevation after nocturnal hypoxia. J Appl Physiol 87:689–698
Auyeung DJ, Kessler FK, Ritter JK (2003) Differential regulation of alternate UDP-glucuronosyltransferase 1A6 gene promoters by hepatic nuclear factor-1. Toxicol Appl Pharmacol 191:156–166
Baumhueter S, Mendel DB, Conley PB, Kuo CJ, Turk C, Graves MK, Edwards CA, Courtois G, Crabtree GR (1990) HNF1 shares three sequence motifs with the POU domain proteins and is identical to LF-B1 and APF. Genes Dev 4:372–379
Baumhueter S, Courtois G, Morgan JG, Crabtree GR (1989) The role of HNF-1 in liver-specific gene expression. Ann NY Acad Sci 557:272–278 (discussion 279)
Bensinger TA, Maisels MJ, Carlson DE, Conrad ME (1973) Effect of low caloric diet on endogenous carbon monoxide production: normal adults and Gilbert’s syndrome. Proc Soc Exp Biol Med 144:417–419
Bernard P, Goudonnet H, Artur Y, Desvergne B, Wahli W (1999) Activation of the mouse TATA-less and human TATA-containing UDP-glucuronosyltransferase 1A1 promoters by hepatocyte nuclear factor 1. Mol Pharmacol 56:526–536
Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP, Chowdhury NR (1995) The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. New Eng J Med 333:1171–1175
Chen J, Cooper AD, Levy-Wilson B (1999) Hepatocyte nuclear factor 1 binds to and transactivates the human but not the rat CYP7A1 promoter. Biochem Biophys Res Commun 260:829–834
Chung I, Bresnick E (1997) Identification of positive and negative regulatory elements of the human cytochrome P4501A2 (CYP1A2) gene. Arch Biochem Biophys 338:220–226
Ciotti M, Chen F, Rubaltelli FF, Owens IS (1998) Coding defect and a TATA box mutation at the bilirubin UDP-glucuronosyltransferase gene cause Crigler-Najjar type I disease. Biochim Biophys Acta 1407:40–50
Gardner-Stephen DA, Mackenzie PI (2007) Isolation of the UDP-glucuronosyltransferase 1A3 and 1A4 proximal promoters and characterization of their dependence on the transcription factor hepatocyte nuclear factor 1α. Drug Metab Dispos 35:116–120
Gregory PA, Lewinsky RH, Gardner-Stephen DA, Mackenzie PI (2004) Coordinate regulation of the human UDP-glucuronosyltransferase 1A8, 1A9, and 1A10 genes by hepatocyte nuclear factor 1alpha and the caudal-related homeogomain protein 2. Mol Pharmacol 65:953–963
Hiraiwa H, Pan CJ, Lin B, Akiyama TE, Gonzalez FJ, Chou JY (2001) A molecular link between the common phenotypes of type I glycogen storage disease and HNF1alpha-null mice. J Biol Chem 276:7963–7967
Ideo G, De Franchis R, Del Ninno E, Dioguardi N (1971) Ethanol increases liver uridine-diphosphate-glucuronyltransferase. Experientia 27:24–25
Liu SY, Gonzalez FJ (1995) Role of the liver-enriched transcription factor HNF-1 alpha in expression of the CYP2E1 gene. DNA Cell Biol 14:285–293
Lundh B, Johansson MB, Mercke C, Cavallin-Stahl E (1972) Enhancement of heme catabolism by caloric restriction in man. Scand J Clin Lab Invest 30:421–427
Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Belanger A, Fournel-Gigleux S, Green M, Hum DW, Iyanagi T, Lancet D, Louisot P, Magdalou J, Chowdhury JR, Ritter JK, Schachter H, Tephly TR, Tipton KF, Nebert DW (1997) The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 7:255–269
Maruo Y, Nishizawa K, Sato H, Doida Y, Shimada M (1999) Association of neonatal hyperbilirubinemia with bilirubin UDP-glucuronosyltransferase polymorphism. Pediatr 103:1224–1227
Maruo Y, Nishizawa K, Sato H, Sawa H, Shimada M (2000) Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate- glucuronosyltransferase gene. Pediatrics 106:E59
Maruo Y, Addario CD, Mori A, Iwai M, Takahashi H, Sato H, Takeuchi Y (2004) Two linked polymorphic mutations (A(TA)7TAA and T-3279G) of UGT1A1 as the principal cause of Gilbert syndrome. Hum Genet 115:525–526
Metz RP, Auyeung DJ, Kessler FK, Ritter JK (2000) Involvement of hepatocyte nuclear factor 1 in the regulation of the UDP-glucuronosyltransferase 1A7 (UGT1A7) gene in rat hepatocytes. Mol Pharmacol 58:319–327
Monaghan G, Ryan M, Seddon R, Hume R, Burchell B (1996) Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet 347:578–581
Monaghan G, McLellan A, McGeehan A, Li Volti S, Mollica F, Salemi I, Din Z, Cassidy A, Hume R, Burchell B (1999) Gilbert’s syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn. J Pediatr 134:441–446
Ostrow JD, Murphy NH (1970) Isolation and properties of conjugated bilirubin and bile. Biochem J 120:311–327
Raijmakers MT, Jansen PL, Steegers EA, Peters WH (2000) Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene. J Hepatol 33:348–351
Radominska-Pandya A, Czemik PJ, Little JM, BattagliaE, Mackenzie PI (1999) Structural and functional studies of UDP-glucuronosyltransferases. Drug Metab Rev 31:817–899
Seppen J, Bosma PJ, Goldhoorn BG, Bakker CT, Chowdhury JR, Chowdhury NR, Jansen PL, Oude Elferink RP (1994) Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J Clin Invest 94:2385–2391
Shih DQ, Screenan S, Munoz KN, Philipson L, Pontoglio M, Yaniv M, Polonsky KS, Stoffel M (2001) Loss of HNF-1α function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes 50:2472–2480
Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH, Owens IS, Negishi M, Sueyoshi T (2001) The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 33:1232–1238
Sugatani J, Yamakawa K, Yoshinari K, Machida T, Takagi H, Mori M, Kakizaki S, Sueyoshi T, Negishi M, Miwa M. (2002) Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia. Biochem Biophys Res Commun 292:492–497
Sugatani J, Yamakawa K, Tonda E, Nishitani S, Yoshinari K, Degawa M, Abe I, Noguchi H, Miwa M (2004) The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics. Biohem. Pharmacol. 67:989–1000
Sugatani J, Sueyoshi T, Negishi M, Miwa M (2005a) Regulation of the human UGT1A1 gene by nuclear receptors CAR, PXR and GR. In: Sies H, Packer L (eds) Conjugation enzymes. Methods in enzymology. Elsevier, Philadelphia, pp 92–104
Sugatani J, Nishitani S, Yamakawa K, Yoshinari K, Sueyoshi T, Nagishi M, Miwa M (2005b) Transcriptional regulation of human UGT1A1 gene expression: Activated glucocorticoid receptor enhances constitutive androstane receptor/pregnane X receptor-mediated UDP-glucuronosyltransferase 1A1 regulation with glucocorticoid receptor-interacting protein 1. Mol Pharmacol 67:845–855
Tukey RH, Strassburg CP (2000) Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40:581–616
Yueh M-F, Huang Y-H, Chen S, Nguyen N, Tukey RH (2003) Involvement of the xenobiotic response element (XRE) in Ah-receptor mediated induction of human UDP-glucuronosyltransferase 1A1. J Biol Chem 278:15001–15006
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-007-0226-y