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Gene Review

UGT1A  -  UDP glucuronosyltransferase 1 family,...

Homo sapiens

Synonyms: GNT1, UGT, UGT1, UGT1A@
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Disease relevance of UGT1A@


High impact information on UGT1A@


Chemical compound and disease context of UGT1A@


Biological context of UGT1A@

  • BACKGROUND: We previously reported that upregulation of glucuronidation activity catalyzed by uridine 5'diphosphoglucuronosyltransferase (UGT) is one of the mechanisms associated with irinotecan hydrochloride/7-ethyl-10-hydroaxycamptothecin (CPT-11/SN-38) resistance [1].
  • Only three major haplotypes were found, including a haplotype consisting of allelic variants of all three isoforms (29% in Caucasians and 22% in Egyptians), all leading to reduced UGT activity [11].
  • The UGT1 gene subfamily consists of a number of UGTs that result from alternate splicing of multiple first exons and share common exons 2-5 [12].
  • Genetic polymorphisms have been identified for almost all the UGT family members [13].
  • Several human hepatic and extrahepatic UGT isozymes have been characterized with respect to their substrate specificity, tissue expression and gene structure [13].

Anatomical context of UGT1A@

  • Glucuronidation of trans-resveratrol by human liver and intestinal microsomes and UGT isoforms [14].
  • Immunochemical identification of UGT isoforms in human small bowel and in caco-2 cell monolayers [15].
  • In cancer tissue, CYP1A activity was decreased in comparison with surrounding healthy mucosa (1.2 +/- 0.9 in tumor tissue vs. 2.2 +/- 0.7 pmol x min[-1] x mg protein[-1], respectively), whereas means and medians of UGT activity were unchanged [16].
  • Michaelis-Menten parameters were determined for entacapone and tolcapone using recombinant human UGT isoforms and human liver microsomes to compare the kinetic properties of the two COMT inhibitors [17].
  • SDS-PAGE and Western blot analysis of UGT1.1-transfected HK293 membrane proteins photolabeled with [11,12-3H]atRA revealed a protein of approximately 56 kDa that was labeled by [3H]atRA, detected by anti-pNP UGT antibody and not present in membranes from nontransfected HK293 cells [18].

Associations of UGT1A@ with chemical compounds

  • Regulation of the UGT1A1 bilirubin-conjugating pathway: Role of a new splicing event at the UGT1A locus [7].
  • Here we report that the two corresponding bilirubin transferases and the phenol transferase are encoded by a novel locus, UGT1, which is also predicted to encode three other bilirubin transferase-like isozymes all having identical carboxyl termini [19].
  • Recessively inherited mutant alleles for the predominant bilirubin isozyme, the HUG-Br1 protein, substituted Arg for Gly at codon 276 (G276R) in exon 1 of UGT1A abolishing a conserved di-glycine [20].
  • Treatment of the resulting cell lines with lipoprotein-deficient serum in the absence and presence of compactin for 5 days resulted in a 1.3- and 2.3-fold, respectively, increase of the UGT enzyme activity towards 4-methylumbelliferone, paralleled by an induction of immunoreactive UGT1A6 protein [21].
  • PURPOSE: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert's syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration [22].

Enzymatic interactions of UGT1A@


Other interactions of UGT1A@

  • In contrast, all UGT isoforms, except for UGT1A3 and UGT1A4, catalyzed O-glucuronidation of 4-HO-TAM [24].
  • Two-hybrid analysis in yeast and mammalian systems demonstrated positive interaction of hUGT1A1 with itself, but not with another UGT isoform, human UGT1A6, which differs only in the N-terminal domain [25].
  • UGT2B7 is the only UGT isoform for which ontogeny has been characterised both in vitro and in vivo, using morphine as the probe drug [9].
  • Among six human UGT isozymes tested, UGT1A1 and 1A3 were capable of catalyzing the glucuronidation of both GFZ and SVA [26].
  • AIM: To investigate the relationship between single nucleotide polymorphisms in the uridine-diphosphoglucuronosyltransferase (UGT) UGT1A7 and UGT1A1 genes and patients suffering from colorectal cancer (CRC) [27].

Analytical, diagnostic and therapeutic context of UGT1A@

  • To confirm the presence of UGT1A1 isoform in human small bowel, to explore the possible absence of UGT1A6 and 2B7 in the organ, and to examine induced Caco-2 cells as a potential model for human intestinal metabolism, Western blot analysis was performed using specific antibodies to the relevant UGT isoforms [15].
  • The study was carried out by immunohistochemistry, using an antiserum recognizing all the UGT1A isoforms [28].
  • In summary, this review focuses on the role of the human UGT genetic polymorphisms in carcinogenesis, chemoprevention and cancer risk [13].
  • Sequence analysis of both UGT1A exon 1 and common exons 2-5 was performed in all patients, leading to the detection of AF170 and a novel mutation (470insT), both residing in UGT1A exon 1 [29].
  • Genetic defects at the UGT1 locus associated with Crigler-Najjar type I disease, including a prenatal diagnosis [30].


  1. UGT1A10 is responsible for SN-38 glucuronidation and its expression in human lung cancers. Oguri, T., Takahashi, T., Miyazaki, M., Isobe, T., Kohno, N., Mackenzie, P.I., Fujiwara, Y. Anticancer Res. (2004) [Pubmed]
  2. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Carlini, L.E., Meropol, N.J., Bever, J., Andria, M.L., Hill, T., Gold, P., Rogatko, A., Wang, H., Blanchard, R.L. Clin. Cancer Res. (2005) [Pubmed]
  3. Coinheritance of variant UDP-glucuronosyl transferase 1A1 gene and glucose-6-phosphate dehydrogenase deficiency in adults with hyperbilirubinemia. Huang, M.J., Yang, Y.C., Yang, S.S., Lin, M.S., Chen, E.S., Huang, C.S. Pharmacogenetics (2002) [Pubmed]
  4. Regulation of the human bilirubin UDP-glucuronosyltransferase gene. Brierley, C.H., Senafi, S.B., Clarke, D., Hsu, M.H., Johnson, E.F., Burchell, B. Adv. Enzyme Regul. (1996) [Pubmed]
  5. Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias. Clarke, D.J., Moghrabi, N., Monaghan, G., Cassidy, A., Boxer, M., Hume, R., Burchell, B. Clin. Chim. Acta (1997) [Pubmed]
  6. Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Xie, W., Yeuh, M.F., Radominska-Pandya, A., Saini, S.P., Negishi, Y., Bottroff, B.S., Cabrera, G.Y., Tukey, R.H., Evans, R.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. Regulation of the UGT1A1 bilirubin-conjugating pathway: Role of a new splicing event at the UGT1A locus. L??vesque, E., Girard, H., Journault, K., L??pine, J., Guillemette, C. Hepatology (2007) [Pubmed]
  8. Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. Chen, S., Beaton, D., Nguyen, N., Senekeo-Effenberger, K., Brace-Sinnokrak, E., Argikar, U., Remmel, R.P., Trottier, J., Barbier, O., Ritter, J.K., Tukey, R.H. J. Biol. Chem. (2005) [Pubmed]
  9. Glucuronidation in humans. Pharmacogenetic and developmental aspects. de Wildt, S.N., Kearns, G.L., Leeder, J.S., van den Anker, J.N. Clinical pharmacokinetics. (1999) [Pubmed]
  10. The novel UGT1 gene complex links bilirubin, xenobiotics, and therapeutic drug metabolism by encoding UDP-glucuronosyltransferase isozymes with a common carboxyl terminus. Owens, I.S., Ritter, J.K., Yeatman, M.T., Chen, F. Journal of pharmacokinetics and biopharmaceutics. (1996) [Pubmed]
  11. Frequent co-occurrence of the TATA box mutation associated with Gilbert's syndrome (UGT1A1*28) with other polymorphisms of the UDP-glucuronosyltransferase-1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians. Köhle, C., Möhrle, B., Münzel, P.A., Schwab, M., Wernet, D., Badary, O.A., Bock, K.W. Biochem. Pharmacol. (2003) [Pubmed]
  12. UDP-glucuronosyltransferases. King, C.D., Rios, G.R., Green, M.D., Tephly, T.R. Curr. Drug Metab. (2000) [Pubmed]
  13. Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer. Nagar, S., Remmel, R.P. Oncogene (2006) [Pubmed]
  14. Glucuronidation of trans-resveratrol by human liver and intestinal microsomes and UGT isoforms. Brill, S.S., Furimsky, A.M., Ho, M.N., Furniss, M.J., Li, Y., Green, A.G., Bradford, W.W., Green, C.E., Kapetanovic, I.M., Iyer, L.V. J. Pharm. Pharmacol. (2006) [Pubmed]
  15. Immunochemical identification of UGT isoforms in human small bowel and in caco-2 cell monolayers. Paine, M.F., Fisher, M.B. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  16. Drug-metabolizing enzymes in pharyngeal mucosa and in oropharyngeal cancer tissue. Ullrich, D., Münzel, P.A., Beck-Gschaidmeier, S., Schröder, M., Bock, K.W. Biochem. Pharmacol. (1997) [Pubmed]
  17. The specificity of glucuronidation of entacapone and tolcapone by recombinant human UDP-glucuronosyltransferases. Lautala, P., Ethell, B.T., Taskinen, J., Burchell, B. Drug Metab. Dispos. (2000) [Pubmed]
  18. Glucuronidation of retinoids by rat recombinant UDP: glucuronosyltransferase 1.1 (bilirubin UGT). Radominska, A., Little, J.M., Lehman, P.A., Samokyszyn, V., Rios, G.R., King, C.D., Green, M.D., Tephly, T.R. Drug Metab. Dispos. (1997) [Pubmed]
  19. A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. Ritter, J.K., Chen, F., Sheen, Y.Y., Tran, H.M., Kimura, S., Yeatman, M.T., Owens, I.S. J. Biol. Chem. (1992) [Pubmed]
  20. Altered coding for a strictly conserved di-glycine in the major bilirubin UDP-glucuronosyltransferase of a Crigler-Najjar type I patient. Ciotti, M., Yeatman, M.T., Sokol, R.J., Owens, I.S. J. Biol. Chem. (1995) [Pubmed]
  21. Treatment of mammalian cells with the endoplasmic reticulum-proliferator compactin strongly induces recombinant and endogenous xenobiotic metabolizing enzymes and 3-hydroxy-3-methylglutaryl-CoA reductase in vitro. McLaughlin, L., Burchell, B., Pritchard, M., Wolf, C.R., Friedberg, T. J. Cell. Sci. (1999) [Pubmed]
  22. Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Rouits, E., Boisdron-Celle, M., Dumont, A., Guérin, O., Morel, A., Gamelin, E. Clin. Cancer Res. (2004) [Pubmed]
  23. The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases. Ethell, B.T., Anderson, G.D., Burchell, B. Biochem. Pharmacol. (2003) [Pubmed]
  24. Quaternary ammonium-linked glucuronidation of trans-4-hydroxytamoxifen, an active metabolite of tamoxifen, by human liver microsomes and UDP-glucuronosyltransferase 1A4. Ogura, K., Ishikawa, Y., Kaku, T., Nishiyama, T., Ohnuma, T., Muro, K., Hiratsuka, A. Biochem. Pharmacol. (2006) [Pubmed]
  25. Homodimerization of human bilirubin-uridine-diphosphoglucuronate glucuronosyltransferase-1 (UGT1A1) and its functional implications. Ghosh, S.S., Sappal, B.S., Kalpana, G.V., Lee, S.W., Chowdhury, J.R., Chowdhury, N.R. J. Biol. Chem. (2001) [Pubmed]
  26. Mechanistic studies on metabolic interactions between gemfibrozil and statins. Prueksaritanont, T., Zhao, J.J., Ma, B., Roadcap, B.A., Tang, C., Qiu, Y., Liu, L., Lin, J.H., Pearson, P.G., Baillie, T.A. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  27. Link between colorectal cancer and polymorphisms in the uridine-diphosphoglucuronosyltransferase 1A7 and 1A1 genes. Tang, K.S., Chiu, H.F., Chen, H.H., Eng, H.L., Tsai, C.J., Teng, H.C., Huang, C.S. World J. Gastroenterol. (2005) [Pubmed]
  28. UDP-glucuronosyltransferases 1A expression in human urinary bladder and colon cancer by immunohistochemistry. Giuliani, L., Ciotti, M., Stoppacciaro, A., Pasquini, A., Silvestri, I., De Matteis, A., Frati, L., Aglianò, A.M. Oncol. Rep. (2005) [Pubmed]
  29. Molecular analysis of patients of Sardinian descent with Crigler-Najjar syndrome type I. Rosatelli, M.C., Meloni, A., Faa, V., Saba, L., Crisponi, G., Clemente, M.G., Meloni, G., Piga, M.T., Cao, A. J. Med. Genet. (1997) [Pubmed]
  30. Genetic defects at the UGT1 locus associated with Crigler-Najjar type I disease, including a prenatal diagnosis. Ciotti, M., Obaray, R., Martín, M.G., Owens, I.S. Am. J. Med. Genet. (1997) [Pubmed]
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