CYP2D6 allele frequencies in Korean population, comparison with East Asian, Caucasian and African populations, and the comparison of metabolic activity of CYP2D6 genotypes

Abstract

Cytochrome P450 (CYP) 2D6 is present in less than about 2% of all CYP enzymes in the liver, but it is involved in the metabolism of about 25% of currently used drugs. CYP2D6 is the most polymorphic among the CYP enzymes. We determined alleles and genotypes of CYP2D6 in 3417 Koreans, compared the frequencies of CYP2D6 alleles with other populations, and observed the differences in pharmacokinetics of metoprolol, a prototype CYP2D6 substrate, depending on CYP2D6 genotype. A total of 3417 unrelated healthy subjects were recruited for the genotyping of CYP2D6 gene. Among them, 42 subjects with different CYP2D6 genotypes were enrolled in the pharmacokinetic study of metoprolol. The functional allele *1 and *2 were present in frequencies of 34.6 and 11.8%, respectively. In decreased functional alleles, *10 was the most frequent with 46.2% and *41 allele was present in 1.4%. The nonfunctional alleles *5 and *14 were present at 4.5 and 0.5% frequency, respectively. The *X × N allele was present at a frequency of 1.0%. CYP2D6*1/*1, *1/*2 and *2/*2 genotypes with normal enzyme activity were present in 12.1%, 8.6% and 1.4% of the subjects, respectively. CYP2D6*5/*5, *5/*14, and *14/*14 genotypes classified as poor metabolizer were only present in 4, 2, and 1 subjects, respectively. Mutant genotypes with frequencies of more than 1% were CYP2D6*1/*10 (32.0%), *10/*10 (22.3%), *2/*10 (11.7%), *5/*10 (3.7%), *1/*5 (2.5%), and *10/*41 (1.2%). The relative clearance of metoprolol in CYP2D6*1/*10, *1/*5, *10/*10, *5/*10, and *5/*5 genotypes were 69%, 57%, 24%, 14% and 9% of CYP2D6*wt/*wt genotype, respectively. These results will be very useful in establishing a strategy for precision medicine related to the genetic polymorphism of CYP2D6.

Population Pharmacokinetic Analysis of Tiropramide in Healthy Korean Subjects

“…In order to amplify a portion of gene containing a SNP by polymerase chain reaction (PCR) from the extracted DNA, each primer was prepared according to the variation of allele. Moreover, the genotypes were determined using appropriate methods that have been reported in the past [5,8,10,11]. We conducted experiments three times to acquire exact genotype data.…”

Sensitive Humans Versus Average Persons in Toxicology

“…One prominent example for genetic polymorphisms is CYP2D6, which metabolizes a variety of pharmaceuticals like anti-depressants, anti-hypertensive drugs, and anti-arrhythmic agents. Altogether it is estimated that CYP2D6 metabolizes about 25% of all pharmaceuticals on the market (Byeon et al 2018). The field of CYP2D6 is rapidly expanding.…”

“…The field of CYP2D6 is rapidly expanding. When Byeon et al wrote their paper, 113 allelic variants of this cytochrome were known (Byeon et al 2018). The linked webpage (http://www.…”

“…pharmvar.org/gene/CYP2D6), in June 2020, indicated almost 140 allelic variants. Of these, nine alleles are most important and they show different levels of activity: *1 and *2 are fully functional alleles, *3, *4, *5, and *6 are nonfunctional alleles and *10, *17, and *41 are reduced functional alleles (Byeon et al 2018). Variant CYP2D6*17 has a frequency of about one third in people of African origin whereas it is almost nonexistent in Caucasians (Ingelman-Sundberg 2001).…”

Benchmarking analysis of deleterious SNP prediction tools on CYP2D6 enzyme

“…Genetic variations are related to dysfunctions in the metabolic capacity of drugs, influencing pharmacokinetics, pharmacodynamics or both, which confer intrinsic differences in drug responses (Ahmed et al, 2016). Therefore, polymorphisms in the CYP2D6 gene could generate four distinct phenotypes based on the metabolizing capacity, including poor, intermediate, extensive and ultra-rapid metabolizers (Arneth, Shams, Hiemke, & Härtter, 2009;Byeon et al, 2018). Hence, CYP2D6 has been considered an important target for pharmacogenomics and pharmacogenetics studies (J. K. Hicks et al, 2013;Ingelman-Sundberg, 2005a;Koski, Ojanperä, Sistonen, Vuori, & Sajantila, 2007).…”