Identification and characterization of a novel CYP2C9 allelic variant in a warfarin-sensitive patient

To determine the genetic basis of the low warfarin dose requirement in a Chinese patient.

Bi-directional sequencing of CYP2C9, VKORC1 and CYP4F2 genes was performed. CYP2C9 variants were highly expressed in yeast and insect-cell microsomes. Three typical CYP2C9 probe drugs were used to evaluate the catalytic activity.

A novel missense mutation (1400 T>C) was identified in CYP2C9 and had been named as new allele *60. When expressed in yeast and insect cells, compared with wild-type enzyme, variant CYP2C9.60 exhibited lower protein expression capacity and showed significantly decreased metabolic activities for the hydroxylation of S-warfarin, tolbutamide and diclofenac.

The novel mutation can greatly decrease the enzymatic activity of the CYP2C9 enzyme both in vitro and in vivo.