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UGT1A6  -  UDP glucuronosyltransferase 1 family,...

Homo sapiens

Synonyms: GNT1, HLUGP, HLUGP1, Phenol-metabolizing UDP-glucuronosyltransferase, UDP-glucuronosyltransferase 1-6, ...
 
 
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Disease relevance of UGT1A6

  • The objective of this study was to assess whether polymorphisms in UGT1A6 and CYP2C9 genes are related to the prevalence of upper gastrointestinal symptoms in cardiovascular patients using acetylsalicylic acid for secondary prevention of ischaemic heart disease [1].
  • CYP2C9 and UGT1A6 genotypes were determined for 474 adenoma cases and 563 controls [2].
  • This genetic variation might impact clinical efficacy or toxicity of drugs metabolized by UGT1A6 [3].
  • Cytochrome P4501A1 (CYP1A1) and the UDP-glucuronosyltransferase isoform UGT1A6 were studied in pharyngeal mucosa and squamous cancer tissue obtained from 27 male subjects (10 healthy nonsmoking volunteers, 10 smokers, and 7 smokers with pharyngeal cancer) [4].
  • However, interactions between UGT1A6 variants or variants of another enzyme that metabolizes nonsteroidal anti-inflammatory drugs (NSAIDs), cytochrome P4502C9 (CYP2C9), and NSAIDs in the prevention of colorectal cancer have not been studied extensively [5].
 

Psychiatry related information on UGT1A6

  • In conclusion, although the identified UGT1A6 polymorphisms did not explain the observed glucuronidation variability, there does seem to be a significant role for environmental factors associated with alcohol consumption [6].
 

High impact information on UGT1A6

  • 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) [7].
  • However, this association was absent in aspirin users who carried the CYP2C9 variant alleles (OR, 0.88; 95% CI, 0.51-1.53) or who were homozygous wild-type UGT1A6 (OR, 0.86; 95% CI, 0.50-1.50) [2].
  • However, maternal liver UGT1A4 and UGT1A6 were dramatically elevated and maintained after birth, indicating that these proteins may play a critical role in maternal metabolism during lactation [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].
 

Chemical compound and disease context of UGT1A6

  • CONCLUSION: Inhibitory effect of troglitazone is weak, however, co-administration of troglitazone might carry a drug concentration into the toxic range when the concentration approaches a threshold of toxicity by an inherent reduction of UGT1A6 activity [9].
  • BACKGROUND AND AIMS: Variant genotypes of uridine diphosphate glucuronsyltransferase isoenzyme 1A6 (UGT1A6) associated with decreased metabolic activity have been associated with an enhanced protective effect of aspirin on the development of colorectal adenomas [5].
  • 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 [10].
  • 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 [11].
 

Biological context of UGT1A6

 

Anatomical context of UGT1A6

 

Associations of UGT1A6 with chemical compounds

 

Other interactions of UGT1A6

  • However, polymorphic expression of UGT1A1 (29%), UGT1A3 (21%), and UGT1A6 (36%) was detected [25].
  • In rabbits, cDNAs encoding proteins homologous to human UGT1A4, UGT1A6, and UGT1A7 have previously been identified [12].
  • Evidence for at least two PAH-inducible UGTs (UGT1A6 and UGT1A9) is presented, which, however, are also constitutively expressed in a tissue- and cell-specific manner [16].
  • Immunoblot analysis demonstrated the presence of UGT1A6 and UGT2B7 in stomach and throughout the intestine [26].
  • Despite the identical primary structure of the C-terminal halves of the UGT1A isoforms, there were marked differences in the respective K(m) values for UDPGA, ranging from 52 microM for UGT1A6 to 1256 microM for UGT1A8 [27].
 

Analytical, diagnostic and therapeutic context of UGT1A6

  • In contrast, the serum from the HCV-patient reacted predominately with UGT1A6, and moreover, the immunoreactivity pattern was different from that of the AIH group [28].
  • The human UGT1A6 cDNA anneals to only a single gene fragment, as displayed by Southern blot analysis, indicating that the UGT1A6 exon 1 sequence is highly conserved [12].
  • PCR technique was used to detect UGT1A6 and CYP1A1 mRNA in the microsomes and mitochondria [29].
  • Furthermore, UGT1A6 lacking the signal peptide (UGT1A6delta sp) was targeted to the endoplasmic reticulum in mammalian cells as shown by immunofluorescence microscopy and was catalytically active with kinetic constants for 4-methylumbelliferone glucuronidation similar to that of the wild-type [30].
  • Immunoblotting analysis using an antibody raised against human UGT1A6 showed that protein staining intensities were different between human and cynomolgus monkey UGT1A6 enzymes in microsomal fractions from livers and yeast cells, although both enzymes were detectable [31].

References

  1. Polymorphisms in genes encoding acetylsalicylic acid metabolizing enzymes are unrelated to upper gastrointestinal health in cardiovascular patients on acetylsalicylic acid. van Oijen, M.G., Huybers, S., Peters, W.H., Drenth, J.P., Laheij, R.J., Verheugt, F.W., Jansen, J.B. British journal of clinical pharmacology. (2005) [Pubmed]
  2. CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk. Bigler, J., Whitton, J., Lampe, J.W., Fosdick, L., Bostick, R.M., Potter, J.D. Cancer Res. (2001) [Pubmed]
  3. Human UGT1A6 pharmacogenetics: identification of a novel SNP, characterization of allele frequencies and functional analysis of recombinant allozymes in human liver tissue and in cultured cells. Nagar, S., Zalatoris, J.J., Blanchard, R.L. Pharmacogenetics (2004) [Pubmed]
  4. 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]
  5. Interactions between CYP2C9 and UGT1A6 polymorphisms and nonsteroidal anti-inflammatory drugs in colorectal cancer prevention. Samowitz, W.S., Wolff, R.K., Curtin, K., Sweeney, C., Ma, K.N., Andersen, K., Levin, T.R., Slattery, M.L. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. (2006) [Pubmed]
  6. UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: I. Identification of polymorphisms in the 5'-regulatory and exon 1 regions, and association with human liver UGT1A6 gene expression and glucuronidation. Krishnaswamy, S., Hao, Q., Al-Rohaimi, A., Hesse, L.M., von Moltke, L.L., Greenblatt, D.J., Court, M.H. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  7. 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]
  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. Inhibitory effect of troglitazone on glucuronidation catalyzed by human uridine diphosphate-glucuronosyltransferase 1A6. Ito, M., Yamamoto, K., Sato, H., Fujiyama, Y., Bamba, T. Eur. J. Clin. Pharmacol. (2001) [Pubmed]
  10. 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]
  11. 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]
  12. Characterization of the UDP-glucuronosyltransferase 1A locus in lagomorphs: evidence for duplication of the UGT1A6 gene. Li, Q., Lamb, G., Tukey, R.H. Mol. Pharmacol. (2000) [Pubmed]
  13. Genetic polymorphisms in UDP-glucuronosyltransferases and glutathione S-transferases and colorectal cancer risk. van der Logt, E.M., Bergevoet, S.M., Roelofs, H.M., van Hooijdonk, Z., te Morsche, R.H., Wobbes, T., de Kok, J.B., Nagengast, F.M., Peters, W.H. Carcinogenesis (2004) [Pubmed]
  14. Genetic polymorphism in the human UGT1A6 (planar phenol) UDP-glucuronosyltransferase: pharmacological implications. Ciotti, M., Marrone, A., Potter, C., Owens, I.S. Pharmacogenetics (1997) [Pubmed]
  15. 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]
  16. Functions and transcriptional regulation of PAH-inducible human UDP-glucuronosyltransferases. Bock, K.W., Gschaidmeier, H., Heel, H., Lehmköster, T., Münzel, P.A., Bock-Hennig, B.S. Drug Metab. Rev. (1999) [Pubmed]
  17. Evaluation of 5-hydroxytryptophol and other endogenous serotonin (5-hydroxytryptamine) analogs as substrates for UDP-glucuronosyltransferase 1A6. Krishnaswamy, S., Hao, Q., Von Moltke, L.L., Greenblatt, D.J., Court, M.H. Drug Metab. Dispos. (2004) [Pubmed]
  18. 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]
  19. Mechanism of rat UDP-glucuronosyltransferase 1A6 induction by oltipraz: evidence for a contribution of the Aryl hydrocarbon receptor pathway. Auyeung, D.J., Kessler, F.K., Ritter, J.K. Mol. Pharmacol. (2003) [Pubmed]
  20. UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations. Lampe, J.W., Bigler, J., Horner, N.K., Potter, J.D. Pharmacogenetics (1999) [Pubmed]
  21. 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]
  22. Human UDP-glucuronosyltransferase 1A1 is the primary enzyme responsible for the N-glucuronidation of N-hydroxy-PhIP in vitro. Malfatti, M.A., Felton, J.S. Chem. Res. Toxicol. (2004) [Pubmed]
  23. UGT1A6 polymorphism and salicylic acid glucuronidation following aspirin. Chen, Y., Kuehl, G.E., Bigler, J., Rimorin, C.F., Schwarz, Y., Shen, D.D., Lampe, J.W. Pharmacogenet. Genomics (2007) [Pubmed]
  24. Interactions with other human UDP-glucuronosyltransferases attenuate the consequences of the Y485D mutation on the activity and substrate affinity of UGT1A6. Kurkela, M., Patana, A.S., Mackenzie, P.I., Court, M.H., Tate, C.G., Hirvonen, J., Goldman, A., Finel, M. Pharmacogenet. Genomics (2007) [Pubmed]
  25. 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]
  26. Glucuronidation of catechols by human hepatic, gastric, and intestinal microsomal UDP-glucuronosyltransferases (UGT) and recombinant UGT1A6, UGT1A9, and UGT2B7. Antonio, L., Xu, J., Little, J.M., Burchell, B., Magdalou, J., Radominska-Pandya, A. Arch. Biochem. Biophys. (2003) [Pubmed]
  27. 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]
  28. 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]
  29. Subcellular expression of UGT1A6 and CYP1A1 responsible for propofol metabolism in human brain. Zhang, S.H., Li, Q., Yao, S.L., Zeng, B.X. Acta Pharmacol. Sin. (2001) [Pubmed]
  30. Expression of a functionally active human hepatic UDP-glucuronosyltransferase (UGT1A6) lacking the N-terminal signal sequence in the endoplasmic reticulum. Ouzzine, M., Magdalou, J., Burchell, B., Fournel-Gigleux, S. FEBS Lett. (1999) [Pubmed]
  31. Functional characterization of human and cynomolgus monkey UDP-glucuronosyltransferase 1A6 enzymes. Hanioka, N., Takeda, Y., Jinno, H., Tanaka-Kagawa, T., Naito, S., Koeda, A., Shimizu, T., Nomura, M., Narimatsu, S. Chem. Biol. Interact. (2006) [Pubmed]
 
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