Glucuronosyltransferases

A recent study used new (unpublished) and published data together to generate 2D-QSAR (Cerius and Dragon) and 3D-QSAR (Catalyst) pharmacophore models for human UGTIAI and UGT1A9 inhibitors as well as for 

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Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates a pharmacoki-... 

Smith PA, Sorich M, McKinnon R, Miners JO. QSAR and pharmacophore modelling approaches for the prediction of UDP-glucuronosyltransferase substrate selectivity and binding. Pharmacologist 2002 44 supplement. 

Smith PA, Sorich MJ, McKinnon RA, Miners JO. Pharmacophore and quantitative structure-activity relationship modeling complementary approaches for the rationalization and prediction of UDP-glucuronosyltransferase 1A4 substrate selectivity. J Med Chem 2003 46 1617-26. 

Sorich MJ, Miners JO, McKinnon RA, Smith PA. Multiple pharmacophores for the investigation of human UDP-glucuronosyltransferase isoform substrate selectivity. Mol Pharmacol 2004 65 301-8. 

Sorich MJ, McKinnon RA, Miners JO, Winkler DA, Smith PA. Rapid prediction of chemical metabolism by human UDP-glucuronosyltransferase isoforms using quantum chemical descriptors derived with the electronegativity equalization method. J Med Chem 2004 47 5311-7. 

Similar to 5-FU, there is a polymorphism associated with irinotecan toxicity. UDP-glucuronosyltransferase (UGT1A1) is an enzyme responsible for the glucuronidation of SN-38 to inactive metabolites, and reduced or deficient levels of this enzyme correlate with irinotecan-induced diarrhea and neutropenia.39 Recently the FDA approved a blood test that detects variations in this gene. This test will assist health care providers in predicting which patients may develop severe toxicities from normal doses of irinotecan and can be ordered prior to patients receiving irinotecan. binotecan is administered as an IV bolus over 60 to 90 minutes in a variety dosing schedules. 

Linnet, K. (2002). Glucuronidation of olanzapine by cDNA-expressed human UDP-glucuronosyltransferases and human liver microsomes. Hum. Psychopharmacol, 17, 233-8. 

Mori, A. etal. (2005).UDP-glucuronosyltransferase lA4polymorphismsinaJapanesepopulation and kinetics of clozapine glucuronidation. Drug Metab. Dispos., 33, 672-5. 

Fisher, M.B., Paine, M.F., Strelevitz, T.J. and Wrighton, S.A. (2001) The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism. Drug Metabolism Reviews, 33, 273-297. 

Basu, N.K., Ciotti, M., Hwang, M.S. et al. (2004) Differential and special properties of the major human UGT1-encoded gastrointestinal UDP-glucuronosyltransferases enhance potential to control chemical uptake. The Journal of Biological Chemistry, 279, 1429-1441. 

Meech, R. and Mackenzie, PI. (1997) Structure and function of uridine diphosphate glucuronosyltransferase. Clinical and Experimental Pharmacology Physiology, 24, 907-915. 

UDP-glucuronosyltransferase gene and irinotecan toxicity a pharmaco-genetic analysis, Cancer Res. 2000, 60, 6921-6926. 

Iyer L, King CD, Whitington PF et al. 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. J Clin Invest 1998 101 847-854. 

Hall D, Ybazeta G, Destro-Bisol G et al. Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates. Pharmacogenetics 1999 9 591-599. 

Lampe JW, Bigler J, Horner NK et al. UDP-glucuronosyltransferase (UGT1A1 28 and UGT1A6 2) polymorphisms in Caucasians and Asians relationships to serum bilimbin concentrations. Pharmacogenetics 1999 9 341-349. 

Three Japanese patients with Crigler-Naj-jar syndrome type I carry an identical nonsense mutation in the gene for UDP-glucuronosyltransferase. Jpn J Hum Genet 1995 40 253-257. 

Akaba K, Kimura T, Sasaki A et al. Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphos-phate-glucuronosyltransferase gene in Japanese. J Hum Genet 1999 44 22-25. 

Maruo Y, Sato H, Yamano T et al. Gilbert syndrome caused by a homozygous missense mutation (Tyr486Asp) of bilirubin UDP-glucuronosyltransferase gene. 

Walle UK and Walle T. 2002. Induction of human UDP-glucuronosyltransferase UGT1A1 by flavonoids-structural requirements. Drug Metab Dispos 30(5) 564-569. 

Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate glucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzyme systems and displaces some drugs from plasma albumin. 

Obermayer-Straub, P., Strassburg, C.R, and Manns, M.R, Target proteins in human autoimmunity cytochromes P450 and UDP-glucuronosyltransferases, Can. J. Gastroenterol., 14, 429, 2000. 

To understand the MOA by which the thyroid tumors are produced, the effect of pyrethrins on rat thyroid gland, thyroid hormone levels, and hepatic thyroxine UDP-glucuronosyltransferase activity was also investigated [128]. The treatment of male rats with 8,000 ppm pyrethrins, female rats with 3,000 and 8,000 ppm pyrethrins, and both sexes with phenobarbital resulted in increased thyroid gland... 

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