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UGT1A1  -  UDP glucuronosyltransferase 1 family,...

Homo sapiens

 
 
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Disease relevance of UGT1A1

 

High impact information on UGT1A1

  • In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome [4].
  • These findings indicate a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinotecan toxicity [5].
  • The affinities for bilirubin of B-UGT1 expressed in COS cells and B-UGT from human liver microsomes were similar with Km of 5.1 +/- 0.9 microM and 7.9 +/- 5.3 microM, respectively [6].
  • Identification of two single base substitutions in the UGT1 gene locus which abolish bilirubin uridine diphosphate glucuronosyltransferase activity in vitro [7].
  • CONCLUSIONS: Our patient represents a case of digenic mixed hyperbilirubinemia-a distinct type of constitutive jaundice resulting from coinherited defects in ABCC2/MRP2 and UGT1A1 genes [8].
 

Chemical compound and disease context of UGT1A1

 

Biological context of UGT1A1

 

Anatomical context of UGT1A1

 

Associations of UGT1A1 with chemical compounds

 

Physical interactions of UGT1A1

 

Enzymatic interactions of UGT1A1

  • In humans, CYP1A2 catalyzed N-hydroxylation and subsequent UGT1A-mediated glucuronidation is a dominant pathway in the metabolism of PhIP [27].
 

Regulatory relationships of UGT1A1

 

Other interactions of UGT1A1

  • METHODS: The full sequence of the UGT1A1 gene was identified for 212 G6PD-deficient and 232 control male neonates by using polymerase chain reaction (PCR) [1].
  • UGT1A10, a newly discovered UGT1A gene product, is expressed only in biliary and not hepatocellular tissue and is also significantly down-regulated in cholangiocellular carcinoma [30].
  • The K(i) values were 3.3 +/- 0.8 micromol/L for UGT1A1 and 31.9 +/- 3.3 micromol/L for UGT1A9 [24].
  • However, polymorphic expression of UGT1A1 (29%), UGT1A3 (21%), and UGT1A6 (36%) was detected [31].
  • Irinotecan is subjected to be shunted between CYP3A4 mediated oxidative metabolism to form two inactive metabolites APC or NPC and tissue carboxylesterase mediated hydrolysis to form SN-38 which is eventually detoxified via glucuronidation by UGT1A1 to form SN-38G [32].
 

Analytical, diagnostic and therapeutic context of UGT1A1

References

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  2. Pharmacogenetics in cancer treatment. Nagasubramanian, R., Innocenti, F., Ratain, M.J. Annu. Rev. Med. (2003) [Pubmed]
  3. 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]
  4. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Tukey, R.H., Strassburg, C.P. Annu. Rev. Pharmacol. Toxicol. (2000) [Pubmed]
  5. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. Iyer, L., King, C.D., Whitington, P.F., Green, M.D., Roy, S.K., Tephly, T.R., Coffman, B.L., Ratain, M.J. J. Clin. Invest. (1998) [Pubmed]
  6. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. Seppen, J., Bosma, P.J., Goldhoorn, B.G., Bakker, C.T., Chowdhury, J.R., Chowdhury, N.R., Jansen, P.L., Oude Elferink, R.P. J. Clin. Invest. (1994) [Pubmed]
  7. Identification of two single base substitutions in the UGT1 gene locus which abolish bilirubin uridine diphosphate glucuronosyltransferase activity in vitro. Erps, L.T., Ritter, J.K., Hersh, J.H., Blossom, D., Martin, N.C., Owens, I.S. J. Clin. Invest. (1994) [Pubmed]
  8. Dual hereditary jaundice: simultaneous occurrence of mutations causing Gilbert's and Dubin-Johnson syndrome. Cebecauerova, D., Jirasek, T., Budisova, L., Mandys, V., Volf, V., Novotna, Z., Subhanova, I., Hrebicek, M., Elleder, M., Jirsa, M. Gastroenterology (2005) [Pubmed]
  9. Induction of UDP-glucuronosyltransferase UGT1A1 by the flavonoid chrysin in the human hepatoma cell line hep G2. Walle, T., Otake, Y., Galijatovic, A., Ritter, J.K., Walle, U.K. Drug Metab. Dispos. (2000) [Pubmed]
  10. Differential UGT1A1 induction by chrysin in primary human hepatocytes and HepG2 Cells. Smith, C.M., Graham, R.A., Krol, W.L., Silver, I.S., Negishi, M., Wang, H., Lecluyse, E.L. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  11. Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) and risk of breast cancer. Adegoke, O.J., Shu, X.O., Gao, Y.T., Cai, Q., Breyer, J., Smith, J., Zheng, W. Breast Cancer Res. Treat. (2004) [Pubmed]
  12. In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Zhang, D., Chando, T.J., Everett, D.W., Patten, C.J., Dehal, S.S., Humphreys, W.G. Drug Metab. Dispos. (2005) [Pubmed]
  13. Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy. Massacesi, C., Terrazzino, S., Marcucci, F., Rocchi, M.B., Lippe, P., Bisonni, R., Lombardo, M., Pilone, A., Mattioli, R., Leon, A. Cancer (2006) [Pubmed]
  14. Effects of prednisone and genetic polymorphisms on etoposide disposition in children with acute lymphoblastic leukemia. Kishi, S., Yang, W., Boureau, B., Morand, S., Das, S., Chen, P., Cook, E.H., Rosner, G.L., Schuetz, E., Pui, C.H., Relling, M.V. Blood (2004) [Pubmed]
  15. Characterization of autoantibodies against uridine-diphosphate glucuronosyltransferase in patients with inflammatory liver diseases. Bachrich, T., Thalhammer, T., Jäger, W., Haslmayer, P., Alihodzic, B., Bakos, S., Hitchman, E., Senderowicz, A.M., Penner, E. Hepatology (2001) [Pubmed]
  16. Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1. Yueh, M.F., Huang, Y.H., Hiller, A., Chen, S., Nguyen, N., Tukey, R.H. J. Biol. Chem. (2003) [Pubmed]
  17. 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]
  18. N-glucuronidation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N_hydroxy-PhIP by specific human UDP-glucuronosyltransferases. Malfatti, M.A., Felton, J.S. Carcinogenesis (2001) [Pubmed]
  19. Risk factors for severe hyperbilirubinemia in neonates. Huang, M.J., Kua, K.E., Teng, H.C., Tang, K.S., Weng, H.W., Huang, C.S. Pediatr. Res. (2004) [Pubmed]
  20. Glucuronidation of etoposide in human liver microsomes is specifically catalyzed by UDP-glucuronosyltransferase 1A1. Watanabe, Y., Nakajima, M., Ohashi, N., Kume, T., Yokoi, T. Drug Metab. Dispos. (2003) [Pubmed]
  21. 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]
  22. Gastrointestinally distributed UDP-glucuronosyltransferase 1A10, which metabolizes estrogens and nonsteroidal anti-inflammatory drugs, depends upon phosphorylation. Basu, N.K., Kubota, S., Meselhy, M.R., Ciotti, M., Chowdhury, B., Hartori, M., Owens, I.S. J. Biol. Chem. (2004) [Pubmed]
  23. 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. Sugatani, J., Nishitani, S., Yamakawa, K., Yoshinari, K., Sueyoshi, T., Negishi, M., Miwa, M. Mol. Pharmacol. (2005) [Pubmed]
  24. Effects of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes. Yong, W.P., Ramirez, J., Innocenti, F., Ratain, M.J. Clin. Cancer Res. (2005) [Pubmed]
  25. Influence of mutations associated with Gilbert and Crigler-Najjar type II syndromes on the glucuronidation kinetics of bilirubin and other UDP-glucuronosyltransferase 1A substrates. Udomuksorn, W., Elliot, D.J., Lewis, B.C., Mackenzie, P.I., Yoovathaworn, K., Miners, J.O. Pharmacogenet. Genomics (2007) [Pubmed]
  26. Inhibition and active sites of UDP-glucuronosyltransferases 2B7 and 1A1. Rios, G.R., Tephly, T.R. Drug Metab. Dispos. (2002) [Pubmed]
  27. The impact of glucuronidation on the bioactivation and DNA adduction of the cooked-food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in vivo. Malfatti, M.A., Ubick, E.A., Felton, J.S. Carcinogenesis (2005) [Pubmed]
  28. Modulation of UDP-glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers. Smith, C.M., Faucette, S.R., Wang, H., LeCluyse, E.L. J. Biochem. Mol. Toxicol. (2005) [Pubmed]
  29. The role of chrysin and the ah receptor in induction of the human UGT1A1 gene in vitro and in transgenic UGT1 mice. Bonzo, J.A., Bélanger, A., Tukey, R.H. Hepatology (2007) [Pubmed]
  30. Differential down-regulation of the UDP-glucuronosyltransferase 1A locus is an early event in human liver and biliary cancer. Strassburg, C.P., Manns, M.P., Tukey, R.H. Cancer Res. (1997) [Pubmed]
  31. Polymorphic expression of the UDP-glucuronosyltransferase UGT1A gene locus in human gastric epithelium. Strassburg, C.P., Nguyen, N., Manns, M.P., Tukey, R.H. Mol. Pharmacol. (1998) [Pubmed]
  32. Lessons learned from the irinotecan metabolic pathway. Ma, M.K., McLeod, H.L. Current medicinal chemistry. (2003) [Pubmed]
  33. 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]
  34. The role of Ah receptor in induction of human UDP-glucuronosyltransferase 1A1. Yueh, M.F., Bonzo, J.A., Tukey, R.H. Meth. Enzymol. (2005) [Pubmed]
 
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