Effect of a conserved mutation in uridine diphosphate glucuronosyltransferase 1A1 and 1A6 on glucuronidation of a metabolite of flutamide.
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.
Ito
Masaki
M
Second Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga, Japan.
Yamamoto
Kazuo
K
Maruo
Yoshihiro
Y
Sato
Hiroshi
H
Fujiyama
Yoshihide
Y
Bamba
Tadao
T
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
D000726:Androgen Antagonists; D005485:Flutamide; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme; C466140:2-amino-5-nitro-4-trifluoromethylphenol glucuronide; C110655:UDP-glucuronosyltransferase, UGT1A6