title: Characterization of a novel CYP2C9 mutation (1009C>A) detected in a warfarin-sensitive patient.
abstract: Warfarin is the most frequently prescribed anticoagulant for the long-term treatment in the clinic. Recent studies have shown that polymorphic alleles within the CYP2C9, VKORC1, and CYP4F2 genes are related to the warfarin dosage requirement. In this study, a novel non-synonymous mutation (1009C>A) in CYP2C9 was detected in a warfarin-hypersensitive patient, while the other two candidate genes were both found to be homozygous for the wild-type alleles. The newly identified point mutation results in an amino acid substitution at position 337 of the CYP2C9 protein (P337T) and has been designated as the novel allele CYP2C9*58. When expressed in insect cell microsomes, the relative intrinsic clearance values of the CYP2C9.58 variant for tolbutamide and losartan were quite similar to those of the typical defective variant CYP2C9.3, whereas the clearance value of CYP2C9.58 for diclofenac was slightly higher than that of another typical defective variant CYP2C9.2. These data suggested that when compared with wild-type CYP2C9.1, the enzymatic activity of the novel allelic variant has been greatly reduced by the 1009C>A mutation. If patients carrying this allele take drugs metabolized by CYP2C9, their metabolic rate might be slower than that of wild-type allele carriers and thus much more attention should be paid to their clinical care.
authors: Shun-Bin
authors: SB
authors: Luo
authors: Chuan-Bao
authors: CB
authors: Li
authors: Da-Peng
authors: DP
authors: Dai
authors: Shuang-Hu
authors: SH
authors: Wang
authors: Zhen-He
authors: ZH
authors: Wang
authors: Pei-Wu
authors: PW
authors: Geng
authors: Jie
authors: J
authors: Cai
authors: Zhe-Li
authors: ZL
authors: Jiang
authors: Cheng-Wei
authors: CW
authors: Pu
authors: Ke
authors: K
authors: Shang
authors: Xin-Min
authors: XM
authors: Yuan
authors: Ya-Po
authors: YP
authors: Cao
authors: Guo-Xin
authors: GX
authors: Hu
authors: Jian-Ping
authors: JP
authors: Cai
mesh_terms: D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000925:Anticoagulants / Q000008:administration & dosage* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008861:Microsomes / Q000201:enzymology; D017354:Point Mutation / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D065729:Cytochrome P-450 CYP2C9