Effect of a conserved mutation in uridine diphosphate glucuronosyltransferase 1A1 and 1A6 on glucuronidation of a metabolite of flutamide

Eur J Clin Pharmacol. 2002 Apr;58(1):11-4. doi: 10.1007/s00228-001-0417-2. Epub 2002 Feb 16.


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.

Conclusion: Patients with Y486D may accumulate excessive 2-amino-5-nitro-4-trifluoromethylphenol, which might lead to unexpected toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / metabolism*
  • Chromatography, Thin Layer
  • Flutamide / metabolism*
  • Glucuronides / genetics*
  • Glucuronides / metabolism*
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism
  • Humans
  • Kinetics
  • Mutation


  • 2-amino-5-nitro-4-trifluoromethylphenol glucuronide
  • Androgen Antagonists
  • Glucuronides
  • Flutamide
  • UDP-glucuronosyltransferase, UGT1A6
  • UGT1A1 enzyme
  • Glucuronosyltransferase