In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population
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...
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| Published in | Basic & clinical pharmacology & toxicology Vol. 117; no. 1; pp. 39 - 43 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
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England
Wiley Subscription Services, Inc
01.07.2015
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| Online Access | Get full text |
| ISSN | 1742-7835 1742-7843 1742-7843 |
| DOI | 10.1111/bcpt.12363 |
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| Abstract | 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. |
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| AbstractList | 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.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. 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. Cytochrome P450 2D6 ( CYP 2D6) is one of the most widely investigated CYP s 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 CYP 2D6 substrates. In this study, wild‐type CYP 2D6, two common allelic variants and 22 newly reported CYP 2D6 isoforms were transiently expressed in 293 FT 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 CYP 2D6 variants, six allelic isoforms ( CYP 2D6.89, CYP 2D6.92, CYP 2D6.93, CYP 2D6.96, 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 CYP 2D6 phenotype prediction and provide valuable information for the study of clinical impact of these newly found CYP 2D6 variants in China. |
| Author | Wang, Shuang‐Hu Hu, Guo‐Xin Cai, Jian‐Ping Dai, Da‐Peng Cai, Jie Geng, Pei‐Wu Hu, Ji‐Hong Hu, Li‐Ming Nie, Jing‐Jing |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25469868$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1038/tpj.2013.2 10.2133/dmpk.DMPK-11-RV-121 10.1038/aps.2013.123 10.1111/bcpt.12159 10.1074/jbc.M511232200 10.1111/bcpt.12093 10.1081/DMR-120023681 10.1097/01.fpc.0000239974.69464.f2 10.1097/00008571-200107000-00005 10.1124/dmd.108.023242 10.2217/pgs.13.160 10.2174/1389200215666140202215316 10.1007/s12010-013-0303-2 10.1097/00008571-199706000-00004 10.1080/10937400903158342 10.2133/dmpk.DMPK-11-RV-090 10.1124/dmd.30.5.595 10.2165/11318030-000000000-00000 10.1038/sj.tpj.6500285 10.1097/FPC.0b013e3283544062 10.1038/tpj.2012.45 10.1002/prot.20399 10.2174/138920011795495286 10.1517/14622416.3.2.229 |
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| Snippet | 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... Cytochrome P450 2D6 ( CYP 2D6) is one of the most widely investigated CYP s related to genetic polymorphisms and is responsible for one‐quarter of the... 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... |
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| SubjectTerms | Asian Continental Ancestry Group - genetics China - epidemiology Cytochrome P-450 CYP2D6 - genetics Cytochrome P-450 CYP2D6 - metabolism Dextromethorphan - metabolism Ethanolamines - metabolism Gene Frequency Genotype HEK293 Cells Humans Mutation Phenotype Substrate Specificity Transfection |
| Title | In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population |
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