Da-Peng Dai1, Chuan-Bao Li2, Shuang-Hu Wang3, Jie Cai4, Pei-Wu Geng3, Yun-Fang Zhou3, Guo-Xin Hu4, Jian-Ping Cai1. 1. The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China. 2. The Clinical Laboratory of Beijing Hospital, Ministry of Health, Beijing 100730, China. 3. The Laboratory of Clinical Pharmacy, the People's Hospital of Lishui, Lishui, Zhejiang 323000, China. 4. Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Abstract
AIM: To determine the genetic basis of the low warfarin dose requirement in a Chinese patient. MATERIALS & METHODS: 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. RESULTS: 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. CONCLUSION: The novel mutation can greatly decrease the enzymatic activity of the CYP2C9 enzyme both in vitro and in vivo.
AIM: To determine the genetic basis of the low warfarin dose requirement in a Chinese patient. MATERIALS & METHODS: 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. RESULTS: 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. CONCLUSION: The novel mutation can greatly decrease the enzymatic activity of the CYP2C9 enzyme both in vitro and in vivo.
Entities:
Keywords:
CYP2C9; allelic variants; drug metabolism; in vitro functional assessment