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UGT1A5  -  UDP glucuronosyltransferase 1 family,...

Homo sapiens

Synonyms: GNT1, UDP-glucuronosyltransferase 1-5, UDP-glucuronosyltransferase 1-E, UDP-glucuronosyltransferase 1A5, UDPGT, ...
 
 
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Disease relevance of UGT1A5

  • 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].
  • 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 [2].
  • 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) [3].
 

High impact information on UGT1A5

  • We have isolated genomic DNA clones containing rat UDP-glucuronosyltransferase family 1 (UGT1) sequences and have shown drug-responsive and tissue-specific alternative expression of multiple first exons (Emi, Y., Ikushiro, S., and Iyanagi, T. (1995) J. Biochem. (Tokyo) 117, 392-399) [4].
  • A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini [5].
  • 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 [5].
  • The relationships of the exons 1 to each other are as follows: UGT1A2p through UGT1A5 comprises a cluster A that is 87-92% identical, and UGT1A7 through UGT1A13p comprises a cluster B that is 67-91% identical [6].
  • Therefore, N-glucuronidation of 1- and 2-naphthylamine (1-NA and 2-NA),4-aminobiphenyl(4-ABP) and their N-hydroxy derivatives was investigated using rat and human liver microsomes and V79 cell-expressed phenol UDP-glucuronosyltransferases (UGT) of the UGT1 gene complex [7].
 

Biological context of UGT1A5

  • The deduced amino acid sequence of the cDNA is 90% similar in sequence to that of a previously characterized form, UGT1A4 and to that of a third form, UGT1A5 whose function in unknown [8].
  • We have established that the nucleotide sequence upstream of the UGT1A5 exon 1 is an ineffective promoter, correlating with the lack of substantial expression of this UGT in human tissues [9].
  • Each isoform of UGT1 results from differential splicing of exon1s to common exon 2-5, and has an unique spectrum of substrate specificity [10].
  • From linkage analyses of the three-point cross test using Elo and En-1 as marker genes, the bilirubin UDPGT gene was mapped at position 37 on chromosome 1 [11].
 

Anatomical context of UGT1A5

  • Low-level UGT1A5 expression was also found in HepG2 and Caco-2 cells as well as human liver [12].
  • We have now detected a low basal level of UGT1A5 expression in cultured human hepatocytes, and treatment with rifampicin or 3-methylcholanthrene increased the level of UGT1A5 mRNA [12].
 

Associations of UGT1A5 with chemical compounds

  • Recombinant UGT1A5, expressed in baculovirus-infected insect cells, exhibited very low rates of 4-methylumbelliferone and scopoletin glucuronidation, whereas 1-hydroxypyrene was a much better substrate for it [12].
  • However, replacing the first 110 amino acids of UGT1A5, a region that may be involved in substrate binding, with the counterpart segment from UGT1A4 did not increase the 4-aminobiphenyl glucuronidation activity [12].
  • Stably expressed human and rat phenol UDP-glucuronosyltransferases (UGTs) of the UGT1 complex (HlugP1, HlugP4 and 3-methylcholanthrene-inducible rat UGT1A1, the latter considered to be an orthologous enzyme to HlugP1) have been used to investigate the role of UGTs in paracetamol glucuronidation [13].
  • Other UGT1 and UGT2 enzymes seem to be responsible for the rest of the troglitazone glucuronidation in humans [14].
  • Inhibitions obtained with chemicals or drugs glucuronidated by either UGT1 or UGT2 families (1-naphtol, 4-hydroxybiphenyl, carvacrol, n-propylgallate, ketoprofen, chloramphenicol, acetylsalicylic acid) indicated that at least two UGT isoforms are involved in propofol glucuronidation [15].
 

Other interactions of UGT1A5

 

Analytical, diagnostic and therapeutic context of UGT1A5

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. UDP-glucuronosyltransferases: gene structures of UGT1 and UGT2 families. Owens, I.S., Basu, N.K., Banerjee, R. Meth. Enzymol. (2005) [Pubmed]
  3. 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]
  4. Xenobiotic responsive element-mediated transcriptional activation in the UDP-glucuronosyltransferase family 1 gene complex. Emi, Y., Ikushiro, S., Iyanagi, T. J. Biol. Chem. (1996) [Pubmed]
  5. 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]
  6. Thirteen UDPglucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. Gong, Q.H., Cho, J.W., Huang, T., Potter, C., Gholami, N., Basu, N.K., Kubota, S., Carvalho, S., Pennington, M.W., Owens, I.S., Popescu, N.C. Pharmacogenetics (2001) [Pubmed]
  7. Glucuronidation of carcinogenic arylamines and their N-hydroxy derivatives by rat and human phenol UDP-glucuronosyltransferase of the UGT1 gene complex. Orzechowski, A., Schrenk, D., Bock-Hennig, B.S., Bock, K.W. Carcinogenesis (1994) [Pubmed]
  8. cDNA cloning and characterization of the human UDP glucuronosyltransferase, UGT1A3. Mojarrabi, B., Butler, R., Mackenzie, P.I. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  9. Isolation of the UDP-Glucuronosyltransferase 1A3 and 1A4 Proximal Promoters and Characterization of Their Dependence on the Transcription Factor Hepatocyte Nuclear Factor 1{alpha}. Gardner-Stephen, D.A., Mackenzie, P.I. Drug Metab. Dispos. (2007) [Pubmed]
  10. Polymorphism of UDP-glucuronosyltransferase and drug metabolism. Maruo, Y., Iwai, M., Mori, A., Sato, H., Takeuchi, Y. Curr. Drug Metab. (2005) [Pubmed]
  11. Mapping of the mouse bilirubin UDP-glucuronosyltransferase gene (Gnt-1) to chromosome 1 by restriction fragment length variations. Sato, H., Sakai, Y., Koiwai, O., Watanabe, T. Biochem. Genet. (1992) [Pubmed]
  12. Human UDP-glucuronosyltransferase 1A5: identification, expression, and activity. Finel, M., Li, X., Gardner-Stephen, D., Bratton, S., Mackenzie, P.I., Radominska-Pandya, A. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  13. Paracetamol glucuronidation by recombinant rat and human phenol UDP-glucuronosyltransferases. Bock, K.W., Forster, A., Gschaidmeier, H., Brück, M., Münzel, P., Schareck, W., Fournel-Gigleux, S., Burchell, B. Biochem. Pharmacol. (1993) [Pubmed]
  14. Characterization of UDP-glucuronosyltransferases (UGTS) involved in the metabolism of troglitazone in rats and humans. Yoshigae, Y., Konno, K., Takasaki, W., Ikeda, T. The Journal of toxicological sciences. (2000) [Pubmed]
  15. Glucuronidation of propofol in microsomal fractions from various tissues and species including humans: effect of different drugs. Le Guellec, C., Lacarelle, B., Villard, P.H., Point, H., Catalin, J., Durand, A. Anesth. Analg. (1995) [Pubmed]
  16. Therapeutic lentivirus-mediated neonatal in vivo gene therapy in hyperbilirubinemic Gunn rats. Nguyen, T.H., Bellodi-Privato, M., Aubert, D., Pichard, V., Myara, A., Trono, D., Ferry, N. Mol. Ther. (2005) [Pubmed]
 
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