CYP2D6 Protein Level Is the Major Contributor to Interindividual Variability in CYP2D6-Mediated Drug Metabolism in Healthy Human Liver Tissue.
CYP2D6 Protein Level Is the Major Contributor to Interindividual Variability in CYP2D6-Mediated Drug Metabolism in Healthy Human Liver Tissue.
复制标题
DOI：
10.1002/cpt.1032
复制
发表时间：
2018-11
影响因子：
6.7
通讯作者：
Jeong H
中科院分区：
文献类型：
--
作者：
Ning M;Duarte JD;Rubin LH;Jeong H
CYP2D6 遗传多态性被认为是 CYP2D6 介导的药物代谢个体间差异较大的主要原因，但无法解释其中很大一部分差异。本研究的目的是评估根据 CYP2D6 基因型估计的 CYP2D6 活性评分 (AS) 预测 CYP2D6 表达和酶活性的能力。对 115 个健康人肝组织样本中的 CYP2D6 基因区域进行测序，以确定其 CYP2D6 AS。此外，还评估了 CYP2D6 酶活性、蛋白质和 mRNA 水平。 CYP2D6 AS 解释了 CYP2D6 活性个体间变异的 23%，但在分配为 AS 1-2 的组织中仅解释了 7.5%。 CYP2D6 蛋白水平被发现是 CYP2D6 活性的主要决定因素，解释了 59% 的变异性。这些发现表明，虽然 CYP2D6 AS 是代谢不良表型的良好预测因子，但其他非遗传因素可能会控制那些没有不良代谢表型的人的 CYP2D6 介导的代谢率。
CYP2D6 genetic polymorphisms are considered a major contributor to the large inter-individual variability in CYP2D6-mediated drug metabolism, but fail to explain significant portion of the variability. The aim of this study was to assess the ability of CYP2D6 activity score (AS) estimated from CYP2D6 genotype to predict CYP2D6 expression and enzyme activity. The CYP2D6 gene region was sequenced in 115 healthy human liver tissue samples to determine their CYP2D6 AS. Additionally, CYP2D6 enzyme activity, protein, and mRNA levels were estimated. CYP2D6 AS explained 23% of the inter-individual variability in CYP2D6 activity, but only 7.5% in tissues assigned AS 1-2. CYP2D6 protein level was found to be the major determinant of CYP2D6 activity, explaining 59% of variability. These findings suggest that while CYP2D6 AS is a good predictor of poor metabolizer phenotype, additional non-genetic factors may govern the rate of CYP2D6-mediated metabolism in those without the poor metabolizer phenotype.
登录
查看更多内容
影响因子：
2.5
作者：
Carlsson, Kristin C.;van de Schootbrugge, Margunn;Hoem, Nils Ove
通讯作者：
Hoem, Nils Ove
影响因子：
2.4
作者：
Scappaticci GB;Regal RE
通讯作者：
Regal RE
影响因子：
2.9
作者：
Colgan S;Faasse K;Martin LR;Stephens MH;Grey A;Petrie KJ
通讯作者：
Petrie KJ
影响因子：
6.8
作者：
AKAIKE, H
通讯作者：
AKAIKE, H
影响因子：
2.2
作者：
Ouellet, D;Bockbrader, HN;Garofalo, E
通讯作者：
Garofalo, E