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Ugt1a1  -  UDP glucuronosyltransferase 1 family,...

Rattus norvegicus

Synonyms: B1, UDP-glucuronosyltransferase 1-1, UDP-glucuronosyltransferase 1A1, UDPGT 1-1, UGT1*1, ...
 
 
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Disease relevance of Ugt1a1

  • The Gunn rat is a mutant strain of Wistar rat which has unconjugated hyperbilirubinemia as a result of the absence of hepatic UDP-glucuronosyltransferase (UDPGT) activity toward bilirubin [1].
  • 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 [2].
  • In behavioural experiments, the B1 antagonist desArg10HOE140, administered by either intrathecal or systemic routes, attenuated Freund's complete adjuvant-induced mechanical hyperalgesia in the inflamed paw, but did not affect mechanical allodynia [3].
  • Twenty-four hours after injection of Freund's complete adjuvant into one hindpaw, there was a significant increase in B1 protein expression (measured by immunohistochemistry) in both ipsilateral and contralateral dorsal root ganglion neurones, whereas axotomy resulted in reduction of B1 protein in ipsilateral dorsal root ganglia [3].
  • Overall, these data suggest that the loss in crystallin mRNAs in response to the development of galactose cataracts follows this order of decline: gamma greater than alpha B greater than alpha A greater than beta B1 [4].
 

High impact information on Ugt1a1

 

Chemical compound and disease context of Ugt1a1

  • Activation of either B1 or B2 bradykinin receptors by kinins released from damaged tissues contributes to the development and maintenance of inflammatory hyperalgesia [3].
  • 6 In summary, we have shown that in endotoxemia activation of B1 receptors causes coronary vasodilation via endothelial prostacyclin release [7].
  • The synthesis and distribution of the kinin B1 and B2 receptors are modified in the hippocampus of rats submitted to pilocarpine model of epilepsy [8].
  • In rats fed a vitamin A-balanced diet, a single injection of l-T3 (500 microg/kg body weight) increased UGT1A6 mRNA expression whereas this hormone decreased UGT1A1 mRNA expression [9].
  • In contrast, the amounts of message for laminin B1 remain identical after 1 week and 4 weeks of cyclosporine administration, despite the development of fibrosis at 4 weeks [10].
 

Biological context of Ugt1a1

  • We therefore made a cDNA library from MC-treated Gunn rat liver mRNA and isolated cDNA clones, using the 4-NP UDPGT cDNA as a probe [11].
  • Three novel cDNAs were identified that had identical 3'-regions of 1362 base pairs containing a single-base deletion in the same position as that of the mutant 4NP-UDPGT cDNA [1].
  • The PB-like inducers, 2,2',4,4',5, 5'-hexachlorobiphenyl (HCB) and 1,1-dichloro-2, 2-bis(p-chlorophenyl)ethane (o,p-DDD), proportionally induced the CYP2B1/2B2 and UDPGT genes and activated the plasmid (HCB = PB > DDD) [12].
  • These results show that chemoprevention by ANIT against PhIP-induced rat mammary carcinogenesis can be explained by a dual action mechanism, i.e. a reduction in metabolic activation by hepatic CYP1A2 and an enhancement of detoxification by 4-NP UDPGT [13].
  • Mapping of rat bilirubin UDP-glucuronosyl-transferase gene (Ugt1a1) to chromosome region 9q35-->q36 [14].
 

Anatomical context of Ugt1a1

  • The size of mRNA in Gunn rats was identical to that of the functionally mature UDPGT mRNA in Wistar rats, but the MC-inducible UDPGT protein was absent from homozygous Gunn rat microsomes [11].
  • Hepatocytes exhibited a marked decline in UGT1A1 activity in the first 4 h of culturing (10% of initial activity) and the recovery took 72 h [15].
  • On the other hand, UDPGT activity towards 4-nitrophenol (4-NP) was enhanced using liver microsomes prepared from rats pretreated with a combination of PhIP and ANIT as compared with those pretreated with PhIP or ANIT alone [13].
  • The steady-state levels of mRNAs coding for two components of basement membranes, the alpha 1 chain of type IV collagen and the B1 chain of laminin, were measured in the kidneys of male CDF rats following the induction of diabetes with streptozotocin for periods of between 2 days and 28 weeks [16].
  • It has been speculated that the B1 isoform might be involved in targeting to the plasma membrane [17].
 

Associations of Ugt1a1 with chemical compounds

  • The Gunn rat is also deficient in UDPGT activities toward phenol substrates, and also toward digitoxigenin-monodigitoxiside [1].
  • Among the isozymes expressed in rat hepatic microsomes, UGT1B1 (54 kDa) of bilirubin cluster was found to be a major form and minor forms were identified as UGT1A1 (53 kDa), UGT1B2 (56 kDa), and UGT1B5 (57 kDa) [18].
  • Marked induction was detected in the cases of dexamethasone, clofibrate, and rifampicin treatments for 96 h both in enzyme activity (178, 176, and 168%) and in UGT1A1 protein level (362, 328, and 250%) [15].
  • The rapid degradation of truncated UGT1A1 protein was inhibited partially but not completely by treating Gunn rat hepatocytes with proteasome inhibitors such as carbobenzoxy-Leu-Leu-leucinal and lactacystin [19].
  • On the other hand, marked elevations of UDPGT activities toward p-nitrophenol (164-281% of control) were observed [20].
 

Regulatory relationships of Ugt1a1

 

Other interactions of Ugt1a1

 

Analytical, diagnostic and therapeutic context of Ugt1a1

References

  1. Molecular basis of multiple UDP-glucuronosyltransferase isoenzyme deficiencies in the hyperbilirubinemic rat (Gunn rat). Iyanagi, T. J. Biol. Chem. (1991) [Pubmed]
  2. 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]
  3. Regulation and function of spinal and peripheral neuronal B1 bradykinin receptors in inflammatory mechanical hyperalgesia. Fox, A., Wotherspoon, G., McNair, K., Hudson, L., Patel, S., Gentry, C., Winter, J. Pain (2003) [Pubmed]
  4. Crystallin mRNA concentrations and distribution in lens of normal and galactosemic rats. Implications in development of sugar cataracts. Wen, Y., Shi, S.T., Unakar, N.J., Bekhor, I. Invest. Ophthalmol. Vis. Sci. (1991) [Pubmed]
  5. Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney. Lee, L.K., Meyer, T.W., Pollock, A.S., Lovett, D.H. J. Clin. Invest. (1995) [Pubmed]
  6. Isolation of multiple normal and functionally defective forms of uridine diphosphate-glucuronosyltransferase from inbred Gunn rats. Roy Chowdhury, N., Gross, F., Moscioni, A.D., Kram, M., Arias, I.M., Roy Chowdhury, J. J. Clin. Invest. (1987) [Pubmed]
  7. Inducible expression of the kinin B1 receptor in the endotoxemic heart: mechanisms of des-Arg9bradykinin-induced coronary vasodilation. McLean, P.G., Perretti, M., Ahluwalia, A. Br. J. Pharmacol. (1999) [Pubmed]
  8. The synthesis and distribution of the kinin B1 and B2 receptors are modified in the hippocampus of rats submitted to pilocarpine model of epilepsy. Argañaraz, G.A., Silva, J.A., Perosa, S.R., Pessoa, L.G., Carvalho, F.F., Bascands, J.L., Bader, M., da Silva Trindade, E., Amado, D., Cavalheiro, E.A., Pesquero, J.B., da Graça Naffah-Mazzacoratti, M. Brain Res. (2004) [Pubmed]
  9. Influence of vitamin A status on the regulation of uridine (5'-)diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT1A6 expression by L-triiodothyronine. Haberkorn, V., Heydel, J.M., Mounie, J., Artur, Y., Goudonnet, H. Br. J. Nutr. (2001) [Pubmed]
  10. Laminin B1 is preferentially expressed in the cortex of rat kidney and is not affected by cyclosporine administration. Artishevsky, A., Adler, S.G., Glassock, R.J., Nast, C.C. J. Lab. Clin. Med. (1992) [Pubmed]
  11. The 3-methylcholanthrene-inducible UDP-glucuronosyltransferase deficiency in the hyperbilirubinemic rat (Gunn rat) is caused by a -1 frameshift mutation. Iyanagi, T., Watanabe, T., Uchiyama, Y. J. Biol. Chem. (1989) [Pubmed]
  12. Phenobarbital induction of CYP2B1/2 in primary hepatocytes: endocrine regulation and evidence for a single pathway for multiple inducers. Ganem, L.G., Trottier, E., Anderson, A., Jefcoate, C.R. Toxicol. Appl. Pharmacol. (1999) [Pubmed]
  13. Effects of alpha-naphthyl isothiocyanate and a heterocyclic amine, PhIP, on cytochrome P-450, mutagenic activation of various carcinogens and glucuronidation in rat liver. Mori, Y., Koide, A., Tatematsu, K., Sugie, S., Mori, H. Mutagenesis (2005) [Pubmed]
  14. Mapping of rat bilirubin UDP-glucuronosyl-transferase gene (Ugt1a1) to chromosome region 9q35-->q36. Nagai, F., Satoh, H., Mori, S., Sato, H., Koiwai, O., Homma, H., Matsui, M. Cytogenet. Cell Genet. (1995) [Pubmed]
  15. In vitro induction of bilirubin conjugation in primary rat hepatocyte culture. Jemnitz, K., Lengyel, G., Vereczkey, L. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  16. Increased steady-state levels of laminin B1 mRNA in kidneys of long-term streptozotocin-diabetic rats. No effect of an aldose reductase inhibitor. Poulsom, R., Kurkinen, M., Prockop, D.J., Boot-Handford, R.P. J. Biol. Chem. (1988) [Pubmed]
  17. Characterization and cellular distribution of the osteoclast ruffled membrane vacuolar H+-ATPase B-subunit using isoform-specific antibodies. Mattsson, J.P., Skyman, C., Palokangas, H., Väänänen, K.H., Keeling, D.J. J. Bone Miner. Res. (1997) [Pubmed]
  18. Identification and analysis of drug-responsive expression of UDP-glucuronosyltransferase family 1 (UGT1) isozyme in rat hepatic microsomes using anti-peptide antibodies. Ikushiro, S., Emi, Y., Iyanagi, T. Arch. Biochem. Biophys. (1995) [Pubmed]
  19. Accelerated degradation of mislocalized UDP-glucuronosyltransferase family 1 (UGT1) proteins in Gunn rat hepatocytes. Emi, Y., Omura, S., Ikushiro, S., Iyanagi, T. Arch. Biochem. Biophys. (2002) [Pubmed]
  20. Effects of the agrochemicals butachlor, pretilachlor and isoprothiolane on rat liver xenobiotic-metabolizing enzymes. Ishizuka, M., Iwata, H., Kazusaka, A., Hatakeyama, S., Fujita, S. Xenobiotica (1998) [Pubmed]
  21. Dicoumarol-sensitive glucuronidation of benzo(a)pyrene metabolites in rat liver microsomes. Segura-Aguilar, J.E., Barreiro, V., Lind, C. Arch. Biochem. Biophys. (1986) [Pubmed]
  22. Characterization of selective induction and alteration of xenobiotic biotransforming enzymes by vanadium during diethylnitrosamine-induced chemical rat liver carcinogenesis. Bishayee, A., Roy, S., Chatterjee, M. Oncol. Res. (1999) [Pubmed]
  23. Toxicity of the heterocyclic amine batracylin: investigation of rodent N-acetyltransferase activity and potential contribution of cytochrome P450 3A. Stevens, G.J., Burkey, J.L., McQueen, C.A. Cell Biol. Toxicol. (2000) [Pubmed]
  24. Induction of UDP-glycosyltransferase family 1 genes in rat liver: different patterns of mRNA expression with two inducers, 3-methylcholanthrene and beta-naphthoflavone. Saarikoski, S.T., Ikonen, T.S., Oinonen, T., Lindros, K.O., Ulmanen, I., Husgafvel-Pursiainen, K. Biochem. Pharmacol. (1998) [Pubmed]
  25. Effects on extrahepatic UDP-glucuronosyltransferases in hypophysectomized rat. Yokota, H., Kunimasa, Y., Shimoyama, Y., Kobayashi, T., Matsumoto, J., Yuasa, A. J. Biochem. (2002) [Pubmed]
  26. Transcriptional regulation by triiodothyronine of the UDP-glucuronosyltransferase family 1 gene complex in rat liver. Comparison with induction by 3-methylcholanthrene. Masmoudi, T., Hihi, A.K., Vázquez, M., Artur, Y., Desvergne, B., Wahli, W., Goudonnet, H. J. Biol. Chem. (1997) [Pubmed]
  27. Differential induction of functional B1-bradykinin receptors along the rat nephron in endotoxin induced inflammation. Marin-Castaño, M.E., Schanstra, J.P., Praddaude, F., Pesquero, J.B., Ader, J.L., Girolami, J.P., Bascands, J.L. Kidney Int. (1998) [Pubmed]
 
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