Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17
文献类型：期刊论文
| 作者 | Shen, Hongwu; He, Minxia M.; Liu, Houfu; Wrighton, Steven A.; Wang, Li; Guo, Bin ; Li, Chuan
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| 刊名 | DRUG METABOLISM AND DISPOSITION
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| 出版日期 | 2007-08 |
| 卷号 | 35期号:8页码:1292-1300 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.107.015354 |
| 文献子类 | Article |
| 英文摘要 | Polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene are a major cause of pharmacokinetic variability in human. Although the poor metabolizer phenotype is known to be caused by two null alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remains mostly unexplained. Thus, the goal of this study was to examine the intrinsic enzymatic differences that exist among the several active CYP2D6 allelic variants. The relative catalytic activities (enzyme kinetics) of three functionally active human CYP2D6 allelic variants, CYP2D6.1, CYP2D6.10, and CYP2D6.17, were systematically investigated for their ability to metabolize a structurally diverse set of clinically important CYP2D6-metabolized drugs [atomoxetine, bufuralol, codeine, debrisoquine, dextromethorphan, (S)-fluoxetine, nortriptyline, and tramadol] and the effects of various CYP2D6-inhibitors [cocaine, (S)-fluoxetine, (S)-norfluoxetine, imipramine, quinidine, and thioridazine] on these three variants. The most significant difference observed was a consistent but substrate-dependent decease in the catalytic efficiencies of cDNA-expressed CYP2D6.10 and CYP2D6.17 compared with CYP2D6.1, yielding 1.32 to 27.9 and 7.33 to 80.4% of the efficiency of CYP2D6.1, respectively. The most important finding from this study is that there are mixed effects on the functionally reduced allelic variants in enzyme- substrate affinity or enzyme- inhibitor affinity, which is lower, higher, or comparable to that for CYP2D6.1. Considering the rather high frequencies of CYP2D6*10 and CYP2D6*17 alleles for Asians and African Americans, respectively, these data provide further insight into ethnic differences in CYP2D6-mediated drug metabolism. However, as with all in vitro to in vivo extrapolations, caution should be applied to the clinical consequences. |
| WOS关键词 | HUMAN CYTOCHROME-P450 ENZYMES ; HUMAN LIVER-MICROSOMES ; IN-VITRO ; CATALYTIC ACTIVITY ; CLINICAL-PRACTICE ; LOW-AFFINITY ; DEBRISOQUINE ; EXPRESSION ; DRUGS ; 2D6 |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000248200000008 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273186]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Li, Chuan |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Grad Sch, Shanghai 200031, Peoples R China 2.Eli Lilly & Co, Dept Drug Disposit, Lilly Res Labs, Indianapolis, IN 46285 USA 3.Chinese Acad Sci, Guangzhou INst Biomed & Hlth, Guangzhou, Peoples R China |
| 推荐引用方式 GB/T 7714 | Shen, Hongwu,He, Minxia M.,Liu, Houfu,et al. Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17[J]. DRUG METABOLISM AND DISPOSITION,2007,35(8):1292-1300. |
| APA | Shen, Hongwu.,He, Minxia M..,Liu, Houfu.,Wrighton, Steven A..,Wang, Li.,...&Li, Chuan.(2007).Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17.DRUG METABOLISM AND DISPOSITION,35(8),1292-1300. |
| MLA | Shen, Hongwu,et al."Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17".DRUG METABOLISM AND DISPOSITION 35.8(2007):1292-1300. |
入库方式： OAI收割
来源：上海药物研究所
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