From Genotype to Phenotype: Cytochrome P450 2D6-Mediated Drug Clearance in Humans
From Genotype to Phenotype: Cytochrome P450 2D6-Mediated Drug Clearance in Humans
复制标题
从基因型到表型：细胞色素 P450 2D6 介导的人体药物清除
DOI：
10.1021/acs.molpharmaceut.6b00920
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发表时间：
2017-03-01
影响因子：
4.9
通讯作者：
Qiao, Hai-Ling
中科院分区：
文献类型：
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作者：
Gao, Jie;Tian, Xin;Qiao, Hai-Ling
基因型变异如何导致表型差异，至今仍是生物学面临的一个挑战。在药物代谢领域，特定细胞色素P4502 D 6（CYP 2D 6）基因型在不同水平（分子、细胞和生物体）产生不同表型的方式是一个重要问题，因为CYP 2D 6活性的差异可能导致药物不良反应。在此，CYP 2D 6的基因型与人肝152微粒体中每克肝的CYP 2D 6和微粒体蛋白的绝对含量一起沿着确定，分子、细胞测定CYP 2D 6的（微粒体、组织、器官）和生物体表型;描述了基因型对CYP 2D 6介导的美沙芬清除（CL）的每种表型的影响，并绘制了CYP 2D 6基因型-表型关系图。我们证明，细胞和有机体CL表型的变化显着大于在分子水平上看到的变化。例如，对于携带1661 CC多态性的个体，最显著的变化发生在器官CL表型（4.17倍），其次是组织（3.75倍），生物体（3.69倍），微粒体（3.09倍）和分子（1.66倍）表型。1661 GG基因型内个体变异系数最大，达104.5%，其次是100 TT、100CT、1661 GC、100CC和1661 CC多态性，分别为102.7%、62.4%、53.5%、49.7%和44.8%。我们的研究使我们能够从分子到生物体水平绘制CYP 2D 6的基因型表型关系，并使我们能够确定每个基因型的表型内个体变异。
How genotypic variation results in phenotypic differences is still a challenge for biology. In the field of drug metabolism, the means by which specific cytochrome P4502D6 (CYP2D6) genotypes yield different phenotypes at various levels (molecular, cellular, and organismal) is an important question, as differences in CYP2D6 activity can contribute to adverse drug reactions. Herein, the genotype of CYP2D6 was determined along with the absolute content of CYP2D6 and microsomal protein per gram of liver in human liver 152 microsomes, the molecular, cellular (microsomal, tissue, organ), and organismal phenotype of CYP2D6 determined; the effect of genotype on each phenotype of CYP2D6-mediated dextromethorphan clearance (CL) was delineated, and the overall genotype-phenotype relationship for CYP2D6 was charted. We demonstrate that changes in the cellular and organismal CL phenotypes are markedly greater than changes seen at the molecular level. With individuals carrying the 1661CC polymorphism, for example, the most noticeable change took place in organ CL phenotype (4.17-fold), followed by tissue (3.75-fold), organism (3.69-fold), microsomal (3.09-fold), and molecular (1.66-fold) phenotypes. In addition, the biggest intragenotype individual coefficient of variation in organismal phenotype was observed in the 1661GG individuals, which reached 104.5%, followed by that of 100TT, 100CT, 1661 GC, 100CC, and 1661CC polymorphisms (102.7%, 62.4%, 53.5%, 49.7%, and 44.8%, respectively). Our study has allowed us to chart the genotype phenotype relationship for CYP2D6 from the molecular to the organismal level as well as allowed us to determine intragenotype individual variation in phenotype with each genotype.