Abstract
Our objectives were to identify CYP2D6 genetic polymorphisms in a Korean population, to compare the allele frequencies with those of other ethnic groups, and to evaluate variant-induced functional variations in dextromethorphan (DM) metabolism in vitro and in vivo. Thirty-eight single nucleotide polymorphisms of CYP2D6 were identified by direct DNA sequencing in 51 Koreans. An extended set of 707 subjects were screened for the identified variants. A group of 202 healthy subjects was subjected to phenotypic analysis on DM metabolism. CYP2D6*10 was found to be the most frequent allele (45.6%), followed by CYP2D6*1 (32.3%), *2 (9.9%), *5 (5.6%), *41 (2.2%), *49 (1.4%), and some other rare alleles (<1%). The newly identified E418K and S183Stop were assigned as CYP2D6*52 and CYP2D6*60, respectively, by the Human P450 (CYP) Allele Nomenclature Committee. Individuals having the CYP2D6*10/*49 genotype (n = 5) exhibited a significant decrease in CYP2D6 metabolic activity compared with those with the CYP2D6*1/*1 genotype (n = 31) (P < 0.019). Variations in CYP2D6 protein levels in liver tissues (n = 49) were observed with CYP2D6 genotypes, and correlation between the CYP2D6 protein content and the activity was significant (r2 = 0.7). Given the importance of CYP2D6 in drug metabolism, subjects with the CYP2D6*10/*49 genotype may benefit from genotype analysis to achieve optimal drug therapy.
Footnotes
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This work was supported in part by the Korea Science and Engineering Foundation [Grant R13-2007-023-00000-0] funded by the Ministry of Education, Science and Engineering, Korea; and the Korea Health 21 R&D Project, Ministry for Health, Welfare, and Family Affairs, Republic of Korea [Grant A030001]. S.-J.L. and S.S.L. contributed equally to this work.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.022368.
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ABBREVIATIONS: PM, poor metabolizer; DM, dextromethorphan; LA, long and accurate; PCR, polymerase chain reaction; UTR, untranslated reaction; SNP, single nucleotide polymorphism; DX, dextrorphan; MR, metabolic ratio; bis-Tris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol.
- Accepted April 9, 2009.
- Received May 14, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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