Genetic Variations of Human
            <i>CYP2D6</i>
            in the Chinese Han Population

Qian, Jianchang; Xu, Xinmin; Hu, Guoxin; Dai, Da‐Peng; Xu, Ren-ai; Hu, Liming; Li, Fanghong; Zhang, Xun; Yang, Jiao; Cai, Jianping

doi:10.2217/pgs.13.160

Cited by 56 publications

(75 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that the allele CYP2D6*92 (1995delC) results in a 654delC mutation in the cDNA sequence and that this mutation is predicted to cause a pre-termination and thus code for a truncated protein with a molecular weight of 25 kDa. Similarly, another allelic variant, CYP2D6*96 (3895C>T), carries one nucleotide change in cDNA at position 1270 (C>T) and results in another pre-stop mutation, 424STOP, at the amino acid level [12]. Based on the expression pattern in mammalian cells, our results revealed that the majority of tested CYP2D6 variants expressed proteins of 55.7 kDa, while the variants CYP2D6*92 and CYP2D6*96 were translated into two truncated proteins of 25 and 47.5 kDa, respectively; these values were equal to their estimated molecular weights ( fig.…”

Section: Resultsmentioning

confidence: 99%

“…As a result, 22 new nonsynonymous, mutated sites were found, and 12 of them were designated as novel alleles (*87-*93, *94A, *94B and *95-*98) by the Human CYP Allele Nomenclature Committee [12]. Considering the fact that there are more than 1.4 billion people living in the mainland of China, it is urgent to investigate the functional characterizations of these newly identified CYP2D6 variants, although the allele frequency of each variant is below 1% [12]. In this study, we expressed all of these novel allelic variants in 293FT cells and systematically evaluated their enzymatic activities towards two typical probing substrates, dextromethorphan and bufuralol.…”

mentioning

confidence: 99%

“…In a recent large-scale, genetic screening study, we sequenced all nine exons of the CYP2D6 gene in 2129 unrelated Chinese individuals. As a result, 22 new nonsynonymous, mutated sites were found, and 12 of them were designated as novel alleles (*87-*93, *94A, *94B and *95-*98) by the Human CYP Allele Nomenclature Committee [12]. Considering the fact that there are more than 1.4 billion people living in the mainland of China, it is urgent to investigate the functional characterizations of these newly identified CYP2D6 variants, although the allele frequency of each variant is below 1% [12].…”

mentioning

confidence: 99%

See 2 more Smart Citations

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

Dai

Geng

Wang

et al. 2015

Basic Clin Pharma Tox

Self Cite

View full text Add to dashboard Cite

Cytochrome P450 2D6 (CYP2D6) is one of the most widely investigated CYPs related to genetic polymorphisms and is responsible for one-quarter of the currently used clinical drugs. We previously detected 22 novel, non-synonymous, mutated sites in the Chinese population, but nothing is known about the functional effects of these mutations in terms of specific CYP2D6 substrates. In this study, wild-type CYP2D6, two common allelic variants and 22 newly reported CYP2D6 isoforms were transiently expressed in 293FT cells, and the enzymatic activities of these variants were systematically assessed using dextromethorphan and bufuralol as the probing substrates. Consequently, 19 and 21 allelic variants were found to exhibit significantly decreased enzymatic activities for dextromethorphan and bufuralol, respectively. Of 22 novel CYP2D6 variants, six allelic isoforms (CYP2D6.89, CYP2D6.92, CYP2D6.93, CYP2D6.96, E215K and R440C) exhibited absent or extremely reduced metabolic activities compared with those observed for the wild-type enzyme. Our in vitro functional data can be useful for CYP2D6 phenotype prediction and provide valuable information for the study of clinical impact of these newly found CYP2D6 variants in China.As one of the most important drug-metabolizing enzymes, cytochrome P450 2D6 (CYP2D6) is responsible for approximately 25% of clinically used drugs including analgesics, antiarrhythmics, antiemetics, antipsychotics, antidepressants, beta-adrenergic blockers and chemotherapeutic/hormone replacement agents [1][2][3]. Similar to other P450 subfamily members, the CYP2D6 gene locus is also highly polymorphic across different ethnic populations and individuals [4]. To date, a total of 105 allelic variants are defined and described in the Human CYP Allele Nomenclature database (http://www.cypalleles.ki.se/cyp2d6.htm). These genetic variants can be associated with increased, decreased or abolished enzymatic functions, which results in differences of up to 30-to 40-fold changes in substrate drug clearance values. Consequently, these differences in CYP2D6 activity have been demonstrated to be prominent contributors to interindividual drug response variability [2,5,6].It has been reported that significant ethnic and geographic differences exist in CYP2D6 alleles [7,8]. For Eastern Asians, only 1-2% of individuals have been found to be poor metabolizers (PMs), and approximately 57% of the Chinese population are intermediate metabolizers (IMs) [9,10]. Polymorphic studies have revealed that the IM allele CYP2D6*10 is predominant in Asian populations with frequencies ranging from 30% to 50% [7,11]. In a recent large-scale, genetic screening study, we sequenced all nine exons of the CYP2D6 gene in 2129 unrelated Chinese individuals. As a result, 22 new nonsynonymous, mutated sites were found, and 12 of them were designated as novel alleles (*87-*93, *94A, *94B and *95-*98) by the Human CYP Allele Nomenclature Committee [12]. Considering the fact that there are more than 1.4 billion people living in the mainland ...

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

Dai

Geng

Wang

et al. 2015

Basic Clin Pharma Tox

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the previous study from our laboratory, we performed a large-scale genetic research of polymorphisms of CYP2D6 in 2129 randomly healthy Chinese Han subjects (Qian et al 2013). Among these novel mutation sites, 22 were nonsynonymous and 12 were named as novel alleles by the Human CYP Allele Nomenclature Committee.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, 22 new nonsynonymous, mutated sites were found (Qian et al 2013), 12 of them were defined as the novel alleles (*87-*93, *94A, *94B and *95-*98) by the Human CYP Allele Nomenclature Committee. Even though the frequency of genetic polymorphism of enzyme CYP2D6 is very low, based on that China has a population of 1.4 billion.…”

Section: Introductionmentioning

confidence: 99%

Effect of 24 cytochrome P450 2D6 variants found in the Chinese population on theN-demethylation of amitriptylinein vitro

Weng

Liang

Zhou

et al. 2016

Pharmaceutical Biology

View full text Add to dashboard Cite

Context: Amitriptyline (AT), one of the tricyclic antidepressants, is still widely used for the treatment of the depression and control of anxiety states and panic disorders in the developing countries. Objective: This study evaluates the catalytic activities of CYP2D6*1, CYP2D6*2, CYP2D6*10 and 22 novel alleles in Han Chinese population and their effects on the N-demethylation of AT in vitro. Materials and methods: CYP2D6*1 and 24 CYP2D6 allelic variants were highly expressed in insect cells, and all variants were characterized using AT as a substrate. Reactions were performed at 37 C with 10-1000 lM substrate for 30 min. We established a HPLC method to quantify the levels of nortriptyline (NT). The kinetic parameters K m , V max and intrinsic clearance (V max /K m ) of NT were calculated. Results: Among the 24 CYP2D6 variants, all variants exhibited decreased intrinsic clearance values compared with wild-type CYP2D6.1. Kinetic parameters of two CYP2D6 variants (CYP2D6*92, *96) could not be determined because of absent enzyme activities. Conclusions: The comprehensive in vitro assessment of CYP2D6 variants provides significant insight into allele-specific activity towards AT in vivo.ARTICLE HISTORY

show abstract

In vitro assessment of 24 CYP2D6 allelic isoforms on the metabolism of methadone

Zhan

Wang

et al. 2016

Drug Testing and Analysis

Self Cite

View full text Add to dashboard Cite

CYP2D6 is an important member of the cytochrome P450 (CYP450) enzyme super family, with at least 100 CYP2D6 alleles being previously identified. Genetic polymorphisms of CYP2D6 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The aim of this study was to clarify the catalytic activities of 24 CYP2D6 alleles on the oxidative in vitro metabolism of methadone. Reactions were incubated with 50-2000 µM methadone for 30 min at 37 °C and terminated by cooling to -80 °C immediately. Methadone and the major metabolite EDDP were analyzed by an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) system. Compared with wild-type CYP2D6*1, most variants showed significantly altered values in V and intrinsic clearance (V /K ). Only three variants (CYP2D6*88, *91 and E215K) exhibited markedly increased intrinsic clearance values, and one variant CYP2D6*94 showed no significant difference. On the other hand, the kinetic parameters of two CYP2D6 variants (CYP2D6*92 and *96) could not be determined because they had no detectable enzyme activity, whereas 18 variants exhibited significantly decreased values. To sum up, this study demonstrated that more attention should be paid in clinical administration of methadone to individuals carrying these CYP2D6 alleles. Copyright © 2016 John Wiley & Sons, Ltd.

show abstract

Genetic Variations of Human CYP2D6 in the Chinese Han Population

Abstract: This study provides the most comprehensive data concerning CYP2D6 polymorphisms in the Chinese Han population to date and increases the number of known alleles; these findings may greatly contribute to the development of personalized medicine for the Chinese Han population.

Cited by 56 publications

References 43 publications

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

Effect of 24 cytochrome P450 2D6 variants found in the Chinese population on theN-demethylation of amitriptylinein vitro

In vitro assessment of 24 CYP2D6 allelic isoforms on the metabolism of methadone

Contact Info

Product

Resources

About