5′-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients-Reference-Cited by-同舟云学术

5′-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients

Published:2004-04-15 Issue:8 Volume:103 Page:3055-3057
ISSN:0006-4971
Container-title:Blood
language:en
Short-container-title:

Author:

Takahashi Harumi¹,Ieiri Ichiro¹,Wilkinson Grant R.¹,Mayo Gail¹,Kashima Toshitaka¹,Kimura Sosuke¹,Otsubo Kenji¹,Echizen Hirotoshi¹

Affiliation:

1. From the Department of Pharmacotherapy, Meiji Pharmaceutical University, Tokyo, Japan; the Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Tottori, Japan; the Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN; and the Department of Cardiovascular Surgery, International Medical Center of Japan, Tokyo, Japan.

Abstract

Abstract White and Japanese patients require different warfarin dosages to achieve therapeutic anticoagulation, but this can be only partly explained by genetic variability in the coding region of CYP2C9—a critical enzyme in the drug's metabolism. Accordingly, analysis of the -2.1-kb 5′-flanking region of CYP2C9 was undertaken in 22 white and 38 Japanese patients whose unbound oral clearance of S-warfarin had been previously determined. Thirteen single nucleotide polymorphisms (SNPs) were identified, some of which were in linkage disequilibrium with functionally defective coding region variants. Those 5′-flanking patterns linked with at least one CYP2C9*3 allele or CYP2C9*2/*3 were associated with reduced CYP2C9 activity and warfarin dose. Japanese patients possessing the wild-type promoter and coding sequences had significantly (P < .01) greater CYP2C9 activity than white patients with the corresponding genotype. In conclusion, either unidentified polymorphisms further upstream in the promoter region or environmental factor(s) account for the differences in the warfarin doses between whites and Japanese. (Blood. 2004;103: 3055-3057)

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Link

http://ashpublications.org/blood/article-pdf/103/8/3055/1698610/zh800804003055.pdf

Reference16 articles.

1. O'Reilly RA. Studies on the optical enantiomorphs of warfarin in man. Clin Pharmacol Ther.1974;16: 348-354.

2. Takahashi H, Wilkinson GR, Caraco Y, et al. Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients. Clin Pharmacol Ther.2003;73: 253-263.

3. Rettie AE, Korzekwa KR, Kunze KL, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol.1992;5: 54-59.

4. Human Cytochrome P450 (CYP) Allele Nomenclature Committee. Available at: http://www.imm.ki.se/CYPalleles/. Accessed January 29, 2004.

5. Takahashi H, Echizen H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J.2003;3: 202-214.