title: Effect of a conserved mutation in uridine diphosphate glucuronosyltransferase 1A1 and 1A6 on glucuronidation of a metabolite of flutamide.
abstract: OBJECTIVE
  We investigated how the conserved mutation (Y486D) changed the kinetic parameters of uridine diphosphate glucuronosyltransferase 1A1 and 1A6 (UGT1A1 and 1A6) for 2-amino-5-nitro-4-trifluoromethylphenol, which is a major metabolite of flutamide, a nonsteroidal antiandrogenic agent.
  
  
  METHODS
  The wild-type or mutant cDNA-expressed UGT was co-incubated with 2-amino-5-nitro-4-trifluoromethylphenol (aglycone) and uridine diphosphate-glucuronic acid (UDP-GA, donor substrate). The glucuronidation of the aglycone was determined.
  
  
  RESULTS
  The maximum velocities of the mutant UGT1A1 and UGT1A6 were about 12% and less than 1% of the corresponding wild-type, respectively. The Michaelis constant (K(M)) for the aglycone of the wild-type UGT1A1 was double that of the mutant, but the K(M) for UDP-GA of the wild-type UGT1A1 was not significantly different from that of the mutant.
  
  
  CONCLUSIONS
  Patients with Y486D may accumulate excessive 2-amino-5-nitro-4-trifluoromethylphenol, which might lead to unexpected toxicity.
authors.affiliation: Second Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ito
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Maruo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fujiyama
authors.forename: Tadao
authors.initials: T
authors.lastname: Bamba
mesh_terms: D000726:Androgen Antagonists / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D005485:Flutamide / Q000378:metabolism*; D020719:Glucuronides / Q000235:genetics* / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009154:Mutation; D000099148:UGT1A1 Enzyme
chemical_list: D000726:Androgen Antagonists; D005485:Flutamide; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme; C466140:2-amino-5-nitro-4-trifluoromethylphenol glucuronide; C110655:UDP-glucuronosyltransferase, UGT1A6