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UGT1A4  -  UDP glucuronosyltransferase 1 family,...

Homo sapiens

Synonyms: Bilirubin-specific UDPGT isozyme 2, GNT1, HUG-BR2, UDP-glucuronosyltransferase 1-4, UDP-glucuronosyltransferase 1-D, ...
 
 
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Disease relevance of UGT1A4

  • Insect cells were co-infected with mixtures containing different combinations of recombinant baculoviruses encoding either UGT1A4 or 1A9Sol [1].
 

High impact information on UGT1A4

 

Biological context of UGT1A4

  • In comparing rabbit and human, it is evident that the UGT1A4 and UGT1A6 gene clusters in rabbit have undergone gene duplication [7].
  • The kinetics of imipramine N-glucuronidation in UGT1A4 Supersomes did not fit the Michaelis-Menten plot, showing a K(m) of >1 mM [8].
  • UGT1A3 is 93% identical to UGT1A4 in primary amino acid sequence [9].
  • Of the compounds screened as inhibitors, hecogenin, alone, was selective; significant inhibition was observed only for UGT1A4 (IC50 1.5 microM) [10].
  • A similar strategy but using probes which correspond to the unique regions of human UDPGT-Br1 and human UDPGT-Br2 showed that the exon 1 of UGT1A and UGT1D encodes the unique region of human UDPGT-Br1, and human UDPGT-Br2 and is located 5.6 and 49 Kb, respectively, upstream of the 4 common exons [11].
 

Anatomical context of UGT1A4

 

Associations of UGT1A4 with chemical compounds

 

Other interactions of UGT1A4

  • In contrast, all UGT isoforms, except for UGT1A3 and UGT1A4, catalyzed O-glucuronidation of 4-HO-TAM [18].
  • Both propofol, a UGT1A9 substrate, and imipramine, a UGT1A4 substrate, inhibited the glucuronidation of nicotine and cotinine by human liver microsomes [16].
  • 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 [19].
  • Characterization of rabbit UDP-glucuronosyltransferase UGT1A7: tertiary amine glucuronidation is catalyzed by UGT1A7 and UGT1A4 [20].
  • We directly sequenced polymerase chain reaction-amplified fragments of the UGT1A4 gene from 100 healthy adult Japanese volunteers and calculated their mutation frequency [21].
 

Analytical, diagnostic and therapeutic context of UGT1A4

  • METHODS: HPLC was used to detect glucuronide conjugates in microsomes from UGT1A4-overexpressing HK293 cells [22].
  • The Vmax/Km ratio for the UGT1A424Pro/48Val variant was significantly (P < or = 0.005) higher than that observed for the wild-type UGT1A4 isoform for both the trans and cis isomers of 4-OH-TAM after normalization for UGT1A4 expression by western blotting [22].
  • The UGT1A4 wild-type cDNA was synthesized by RT-PCR using normal human liver total RNA [22].

References

  1. The interactions between the N-terminal and C-terminal domains of the human UDP-glucuronosyltransferases are partly isoform-specific, and may involve both monomers. Kurkela, M., Hirvonen, J., Kostiainen, R., Finel, M. Biochem. Pharmacol. (2004) [Pubmed]
  2. Variation of hepatic glucuronidation: Novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4. Ehmer, U., Vogel, A., Schütte, J.K., Krone, B., Manns, M.P., Strassburg, C.P. Hepatology (2004) [Pubmed]
  3. Correlation between UDP-glucuronosyltransferase genotypes and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronidation phenotype in human liver microsomes. Wiener, D., Fang, J.L., Dossett, N., Lazarus, P. Cancer Res. (2004) [Pubmed]
  4. 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]
  5. Pharmacophore and quantitative structure-activity relationship modeling: complementary approaches for the rationalization and prediction of UDP-glucuronosyltransferase 1A4 substrate selectivity. Smith, P.A., Sorich, M.J., McKinnon, R.A., Miners, J.O. J. Med. Chem. (2003) [Pubmed]
  6. 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]
  7. 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]
  8. Imipramine N-glucuronidation in human liver microsomes: biphasic kinetics and characterization of UDP-glucuronosyltransferase isoforms. Nakajima, M., Tanaka, E., Kobayashi, T., Ohashi, N., Kume, T., Yokoi, T. Drug Metab. Dispos. (2002) [Pubmed]
  9. Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Green, M.D., King, C.D., Mojarrabi, B., Mackenzie, P.I., Tephly, T.R. Drug Metab. Dispos. (1998) [Pubmed]
  10. Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) "probes" for human udp-glucuronosyltransferases. Uchaipichat, V., Mackenzie, P.I., Elliot, D.J., Miners, J.O. Drug Metab. Dispos. (2006) [Pubmed]
  11. UDPGT cDNA expression and UDPGT1 in human liver. Sheen, Y.Y., Owens, I.S., Kim, S.S., Kim, J.E. The Journal of toxicological sciences. (1998) [Pubmed]
  12. Quaternary ammonium-linked glucuronidation of tamoxifen by human liver microsomes and UDP-glucuronosyltransferase 1A4. Kaku, T., Ogura, K., Nishiyama, T., Ohnuma, T., Muro, K., Hiratsuka, A. Biochem. Pharmacol. (2004) [Pubmed]
  13. 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]
  14. Characterization of afloqualone N-glucuronidation: species differences and identification of human UDP-glucuronosyltransferase isoform(s). Kaji, H., Kume, T. Drug Metab. Dispos. (2005) [Pubmed]
  15. N-glucuronidation of nicotine and cotinine in human: formation of cotinine glucuronide in liver microsomes and lack of catalysis by 10 examined UDP-glucuronosyltransferases. Ghosheh, O., Hawes, E.M. Drug Metab. Dispos. (2002) [Pubmed]
  16. N-glucuronidation of nicotine and cotinine by human liver microsomes and heterologously expressed UDP-glucuronosyltransferases. Kuehl, G.E., Murphy, S.E. Drug Metab. Dispos. (2003) [Pubmed]
  17. 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]
  18. 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]
  19. 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]
  20. Characterization of rabbit UDP-glucuronosyltransferase UGT1A7: tertiary amine glucuronidation is catalyzed by UGT1A7 and UGT1A4. Bruck, M., Li, Q., Lamb, J.G., Tukey, R.H. Arch. Biochem. Biophys. (1997) [Pubmed]
  21. UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation. Mori, A., Maruo, Y., Iwai, M., Sato, H., Takeuchi, Y. Drug Metab. Dispos. (2005) [Pubmed]
  22. Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants. Sun, D., Chen, G., Dellinger, R.W., Duncan, K., Fang, J.L., Lazarus, P. Breast Cancer Res. (2006) [Pubmed]
 
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