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 (KM) for the aglycone of the wild-type UGT1A1 was double that of the mutant, but the KM 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.
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Accepted in revised form: 3 December 2001
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Ito, M., Yamamoto, K., Maruo, Y. et al. Effect of a conserved mutation in uridine diphosphate glucuronosyltransferase 1A1 and 1A6 on glucuronidation of a metabolite of flutamide. Eur J Clin Pharmacol 58, 11–14 (2002). https://doi.org/10.1007/s00228-001-0417-2
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DOI: https://doi.org/10.1007/s00228-001-0417-2