Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans.
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 (r(2) = 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.
Lee
Su-Jun
SJ
Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, 633-165 Gaegum-Dong, Jin-Gu, Busan 614-735, Korea.
Lee
Sang Seop
SS
Jung
Hyun-Ju
HJ
Kim
Ho-Sook
HS
Park
Soo-Jin
SJ
Yeo
Chang-Woo
CW
Shin
Jae-Gook
JG
D020121:5' Untranslated Regions; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D065702:Cytochrome P-450 CYP2B6; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D003915:Dextromethorphan; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D008297:Male; D008745:Methylation; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
D020121:5' Untranslated Regions; D003915:Dextromethorphan; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D019389:Cytochrome P-450 CYP2D6; D010089:Oxidoreductases, N-Demethylating