Glucuronidation enzymes

Villeneuve L, Girard H, Fortier LC et al. Novel functional polymorphisms in the UGT1A7 and UGT1A9 glucuronidating enzymes in Caucasian and African-American subjects and their impact on the metabolism of 7-ethyl-10-hydroxycamptothecin and flavopiridol anticancer drugs. J Pharmacol Exp Ther 2003 307 117-128. 

De Leon J. Glucuronidation enzymes, genes and psychiatry. Int J Neuropsychopharmacol 2003 6 57-72. 

O Connor KA, Brindle E, Hohnan DJ> Klein NA, Soules MR, Campbell KL, et al. Urinary estrone conjugate and pregnanediol 3-glucuronide enzyme immunoassays for population research. Clin Chem 2003 49 1139-48. 

Glucuronyl transferases A group of enzymes that catalyze the formation of conjugates between glucuronide and a xenobiotic (usually a phase I metabolite). 

Polyphenols and flavanoids in rat liver microsomal fractions have been demonstrated to inhibit glucuronidation of estrone and estradiol in vitro (Zhu et al, 1998). In addition, flavonoids have also been found to induce phase I and II enzymes in rats including UDP-glucuronosyl transferase (Seiss et al, 1996). However, the effects of phytoestrogens have not been evaluated for either their inhibition or induction of glucuronosyl transferase activity. 

Hepatic metabolism No Yes oxidation and hydroxylation induces liver enzymes to increase its metabolism and other drugs Yes oxidation and conjugation Yes oxidation and glucuronide conjugation Yes glucuronic acid conjugation Induces its own metabolism in normal volunteers... 

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. 

These incubations are often carried out at 37 °C for 1-2 h. At different time points, 20-200 /aL of incubation mixture is withdrawn from each incubation and mixed with equal volume of ice-cold acetonitrile by vortexing. For preparation of acyl glucuronide, ice-cold acetonitrile containing 1% of formic acid is used to minimize acyl-migration [3,14]. After centrifugation at 13 000 rpm for 5-15 min, the supernatant (10-30 /aU) is analyzed by high-performance liquid chromatography (HPUC)-UV-MS. The metabolite of interest is identified based on HPLC retention time, UV spectrum and MS/MS data. Conversion yield is estimated based on UV absorption peak areas. A suitable in vitro enzyme system for scale-up is then... 

Metabolite biosynthesis has demonstrated its utility in drug metabolite preparation and characterization, and contributed to drag discovery and development. Although metabolite biosynthesis is a prerequisite step for metabolite structure elucidation in many cases, it is complementary to chemical synthesis in large-scale metabolite preparations. The merits for using these techniques should be determined on a case-by-case fashion. New techniques, such as recombinant enzyme and microbial glucuronidation systems, would have a great impact on the field. 

Stevenson, D.E. and Hubl, U. (1999) Optimization of /3-D-glucuronide synthesis using UDP-glucuronyl transferase Enzyme and Microbial Technology 24, 388-396. 

SN-38 glucuronidation is catalyzed by the polymorphic UDP-glucuronosyltransfer-ase 1A1 (UGT1A1) enzyme, which is responsible for bilirubin glucuronidation... 

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