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UGT1A8  -  UDP glucuronosyltransferase 1 family,...

Homo sapiens

Synonyms: GNT1, UDP-glucuronosyltransferase 1-8, UDP-glucuronosyltransferase 1-H, UDP-glucuronosyltransferase 1A8, UDPGT, ...
 
 
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Disease relevance of UGT1A8

  • This study reports the molecular characterisation of the bilirubin UDP-glucuronosyl-transferase gene (UGT1) in a group of patients of Sardinian descent with Crigler-Najjar syndrome type I and their relatives [1].
  • A total of 115 male adults with unconjugated hyperbilirubinemia were divided into six subgroups according to their glucose-6-phosphate dehydrogenase (G6PD) status (normal and deficient) and UDP-glucuronosyl transferase 1 (UGT1) A1 genotypes (heterozygous variation, compound heterozygous variation and homozygous variation) [2].
  • Treatment of humans or hepatoma cell lines with drugs such as phenobarbital causes the induction of hepatic bilirubin UGT by increased transcription from the UGT1 gene [3].
  • In human, rat, and mice, a UGT1 complex locus provides for developmental-, inducer-, and cell-specific synthesis of a family of chemical-detoxifying isozymes, UDP-glucuronosyltransferases, which prevent toxicities, mutagenesis, and/or carcinogenesis [4].
  • In this study, UGT1 and UGT2 gene expression was investigated in human oesophageal epithelium and squamous-cell carcinoma in addition to the characterization of individual UGT isoforms using recombinant protein [5].
 

High impact information on UGT1A8

  • BACKGROUND & AIMS: Approximately 13% of patients with chronic hepatitis D virus (HDV) infection have liver-kidney microsomal antibodies type 3 (LKM-3) directed against family 1 uridine 5'-diphosphate-glucuronosyl-transferases (UGT-1) [6].
  • Furthermore, a >12-fold decreased intrinsic clearance of the *1 proteins was induced by selected amino acid substitutions in UGT1A8 (*3 C277Y) and UGT1A9 (*3 M33T) [7].
  • In Tg-UGT1 mice, the UGT1A proteins are differentially expressed in the liver and gastrointestinal tract [8].
  • Induction of UGT1A1 by PCN and TCDD is believed to be highly dependent upon glucocorticoids, because submicromolar concentrations of dexamethasone actively promote PCN and TCDD induction of UGT1A1 in Tg-UGT1 primary hepatocytes [8].
  • The human UDP-glucuronosyltransferase 1 (UGT1) locus spans nearly 200 kb on chromosome 2 and encodes nine UGT1A proteins that play a prominent role in drug and xenobiotic metabolism [8].
 

Biological context of UGT1A8

 

Anatomical context of UGT1A8

 

Associations of UGT1A8 with chemical compounds

 

Regulatory relationships of UGT1A8

  • In addition, Cdx2 was shown to cooperate with HNF1alpha to synergistically activate the UGT1A8, -1A9, and -1A10 promoters [9].
 

Other interactions of UGT1A8

  • In addition, the expression of extrahepatic UGT1A10 and UGT1A8 was demonstrated [21].
  • UGT1A8 was found to be closely related to gastric UGT1A7 with a 93.8% identity of first exon sequences [21].
  • The involvement of UGT1A1 and UGT1A8/9 was confirmed from studies using cDNA expressed human UGT cell lines [22].
  • Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid [23].
 

Analytical, diagnostic and therapeutic context of UGT1A8

  • Lysates of HK293 cells expressing UGT1A8 revealed the expression of a protein with a molecular mass of 56 kDa by Western blot analysis [24].
  • A cDNA with a complete UGT1A8 coding region was amplified from total human ileal RNA by reverse transcriptase-polymerase chain reaction and inserted into the mammalian expression vector, pcDNA3 [24].
  • Genetic defects at the UGT1 locus associated with Crigler-Najjar type I disease, including a prenatal diagnosis [25].
  • Using the hUGT1-specific antibodies, the subcellular localization of hUGT1 in the Golgi membrane was demonstrated by immunofluorescence microscopy and subcellular fractionation [26].
  • These studies led us to develop a simple procedure, based on Percoll density gradient centrifugation, for preparing functional Golgi vesicles from the hUGT1-transformed Had-1 cells, that will facilitate future biochemical analyses of the UDP-galactose transporter for the elucidation of its structure-function relationship [26].

References

  1. 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]
  2. 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]
  3. 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]
  4. UDP-glucuronosyltransferases: gene structures of UGT1 and UGT2 families. Owens, I.S., Basu, N.K., Banerjee, R. Meth. Enzymol. (2005) [Pubmed]
  5. Regulation and function of family 1 and family 2 UDP-glucuronosyltransferase genes (UGT1A, UGT2B) in human oesophagus. Strassburg, C.P., Strassburg, A., Nguyen, N., Li, Q., Manns, M.P., Tukey, R.H. Biochem. J. (1999) [Pubmed]
  6. Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis. Strassburg, C.P., Obermayer-Straub, P., Alex, B., Durazzo, M., Rizzetto, M., Tukey, R.H., Manns, M.P. Gastroenterology (1996) [Pubmed]
  7. Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone. Thibaudeau, J., Lépine, J., Tojcic, J., Duguay, Y., Pelletier, G., Plante, M., Brisson, J., Têtu, B., Jacob, S., Perusse, L., Bélanger, A., Guillemette, C. Cancer Res. (2006) [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. Coordinate regulation of the human UDP-glucuronosyltransferase 1A8, 1A9, and 1A10 genes by hepatocyte nuclear factor 1alpha and the caudal-related homeodomain protein 2. Gregory, P.A., Lewinsky, R.H., Gardner-Stephen, D.A., Mackenzie, P.I. Mol. Pharmacol. (2004) [Pubmed]
  10. Cloning and characterization of the human UDP-glucuronosyltransferase 1A8, 1A9, and 1A10 gene promoters: differential regulation through an interior-like region. Gregory, P.A., Gardner-Stephen, D.A., Lewinsky, R.H., Duncliffe, K.N., Mackenzie, P.I. J. Biol. Chem. (2003) [Pubmed]
  11. Hepatic expression of the UGT1A9 gene is governed by hepatocyte nuclear factor 4alpha. Barbier, O., Girard, H., Inoue, Y., Duez, H., Villeneuve, L., Kamiya, A., Fruchart, J.C., Guillemette, C., Gonzalez, F.J., Staels, B. Mol. Pharmacol. (2005) [Pubmed]
  12. Hepatocyte nuclear factor1 transcription factors are essential for the UDP-glucuronosyltransferase 1A9 promoter response to hepatocyte nuclear factor 4alpha. Gardner-Stephen, D.A., Mackenzie, P.I. Pharmacogenet. Genomics (2007) [Pubmed]
  13. Identification and functional characterization of UDP-glucuronosyltransferases UGT1A8*1, UGT1A8*2 and UGT1A8*3. Huang, Y.H., Galijatovic, A., Nguyen, N., Geske, D., Beaton, D., Green, J., Green, M., Peters, W.H., Tukey, R.H. Pharmacogenetics (2002) [Pubmed]
  14. Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10. Watanabe, Y., Nakajima, M., Yokoi, T. Drug Metab. Dispos. (2002) [Pubmed]
  15. Amino acid residue ILE211 is essential for the enzymatic activity of human UDP-glucuronosyltransferase 1A10 (UGT1A10). Martineau, I., Tchernof, A., Bélanger, A. Drug Metab. Dispos. (2004) [Pubmed]
  16. Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance. Kemp, D.C., Fan, P.W., Stevens, J.C. Drug Metab. Dispos. (2002) [Pubmed]
  17. Regulation of UDP glucuronosyltransferases in the gastrointestinal tract. Gregory, P.A., Lewinsky, R.H., Gardner-Stephen, D.A., Mackenzie, P.I. Toxicol. Appl. Pharmacol. (2004) [Pubmed]
  18. Involvement of multiple UDP-glucuronosyltransferase 1A isoforms in glucuronidation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin in human liver microsomes. Nakajima, M., Sakata, N., Ohashi, N., Kume, T., Yokoi, T. Drug Metab. Dispos. (2002) [Pubmed]
  19. Identification of uridine diphosphate glucuronosyltransferases involved in the metabolism and clearance of mycophenolic acid. Mackenzie, P.I. Therapeutic drug monitoring. (2000) [Pubmed]
  20. Kinetic characterization of the 1A subfamily of recombinant human UDP-glucuronosyltransferases. Luukkanen, L., Taskinen, J., Kurkela, M., Kostiainen, R., Hirvonen, J., Finel, M. Drug Metab. Dispos. (2005) [Pubmed]
  21. Expression of the UDP-glucuronosyltransferase 1A locus in human colon. Identification and characterization of the novel extrahepatic UGT1A8. Strassburg, C.P., Manns, M.P., Tukey, R.H. J. Biol. Chem. (1998) [Pubmed]
  22. Identification of UDP-glucuronosyltransferases involved in the human hepatic metabolism of GV150526, a novel glycine antagonist. Gilissen, R.A., Barnaby, R.J., Kajbaf, M. Drug metabolism and drug interactions. (2000) [Pubmed]
  23. Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid. Bernard, O., Tojcic, J., Journault, K., Perusse, L., Guillemette, C. Drug Metab. Dispos. (2006) [Pubmed]
  24. Cloning and expression of human UDP-glucuronosyltransferase (UGT) 1A8. Cheng, Z., Radominska-Pandya, A., Tephly, T.R. Arch. Biochem. Biophys. (1998) [Pubmed]
  25. 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]
  26. Expression of the human UDP-galactose transporter in the Golgi membranes of murine Had-1 cells that lack the endogenous transporter. Yoshioka, S., Sun-Wada, G.H., Ishida, N., Kawakita, M. J. Biochem. (1997) [Pubmed]
 
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