Molecular basis of interindividual variability in CYP2D6-mediated drug metabolism

CYP2D6介导的药物代谢个体差异的分子基础

• 批准号: 9099936
• 负责人: Hyunyoung Jeong
• 金额: $ 31.36万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099936
• 关键词: CYP2D6 gene; CYP3A4 gene; Caucasians; Clinical; Complement; Data; Development; Diet; Dose; Environmental Risk Factor; Enzymes; Exhibits; Foundations; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; Health; Hepatic; Human; Individual; Knowledge; Lead; Liver; Mediating; Messenger RNA; Molecular; Mus; Outcome; Persons; Pharmaceutical Preparations; Phenotype; Play; Population; Reaction; Regulation; Research; Risk; Role; Testing; Tissues; Transcriptional Regulation; Transgenic Organisms; Work; base; design; differential expression; drug market; drug metabolism; enzyme activity; improved; novel; novel marker; response; transcription factor

 DESCRIPTION (provided by applicant): Unintentional drug over- or under-dosing is an enormous clinical problem. The large interindividual variability in CYP2D6-mediated drug metabolism is a critical contributor to this problem, as it is responsible for the unpredictable occurrence of adverse drug outcomes in response to a given dose of a CYP2D6 substrate. It is known that genetic polymorphisms of CYP2D6 partially explain the variability, especially for the poor metabolizer phenotype; however, they fail to explain the majority of variability in the remaining population (~90%). Accumulating evidence strongly indicates that differential regulation of CYP2D6 at the transcriptional level plays a key role in determining CYP2D6-mediated drug metabolism. In healthy human liver tissues, mRNA levels of CYP2D6 were highly correlated with the enzyme's activity. The level of correlation was similar to that for CYP3A4, a gene whose expression is controlled mainly at the transcriptional level. Despite this evidence, factors governing CYP2D6 transcription are poorly understood. Thus, there is a substantial gap in our understanding of the interindividual variability that lead to adverse drug reactions or drug inefficacy. The long-term goal of our research is to develop approaches to better predict the highly variable CYP2D6 activity in individuals. Our hypothesis is that genetic and environmental factors regulate the expression/activity of a specific transcription factor, small heterodimer partner (SHP), which in turn alters CYP2D6 expression. We further hypothesize that this is in part responsible for the interindividual variability in CYP2D6 expression. Our hypothesis is based on our recent finding in CYP2D6-humanized transgenic (Tg-CYP2D6) mice that SHP represses CYP2D6 expression. Moreover, compounds enhancing SHP expression repress hepatic CYP2D6 expression, and SHP and CYP2D6 expression is negatively correlated in human liver tissues. These data strongly suggest that SHP plays a key role in regulating CYP2D6 expression and that differential expression of SHP leads to CYP2D6 variability. To test our hypothesis, we propose the following specific aims: (1) Determine the extent to which SHP modulators cause alterations of CYP2D6 expression in Tg-CYP2D6 mice, and (2) Identify SHP modulators that explain CYP2D6 variability in human liver tissues. Current efforts to predict CYP2D6 activity rely exclusively on the CYP2D6 genotypes and fail to explain CYP2D6 variability in the majority of the population. The proposed work is expected to reveal previously unknown contributors to CYP2D6 variability (namely extrinsic and genetic factors controlling the expression and/or activity of SHP) and, thus, improve the ability to predict CYP2D6 activity. We believe this will ultimately lead to the development of strategies to minimize the risk of dangerous drug over- and under-dosing with CYP2D6 substrates.

 描述（适用提供）：无意的药物过度或剂量不足是一个增强的临床问题。 CYP2D6介导的药物代谢的个体间差异很大，是该问题的关键因素，因为它是响应给定剂量的CYP2D6底物的不良药物结果的不良发生。众所周知，CYP2D6的遗传多态性部分解释了变异性，尤其是对于不良的代谢表型而言。但是，他们无法解释其余人群中的大多数变异性（〜90％）。积累的证据强烈表明，转录水平的CYP2D6的差异调节在确定CYP2D6介导的药物代谢方面起着关键作用。在健康的人肝组织中，CYP2D6的mRNA水平与酶的活性高度相关。相关水平与CYP3A4的相关水平相似，CYP3A4的表达主要在转录水平上控制。尽管有这些证据，但对CYP2D6转录的因素知之甚少。这是我们对个体间变异性的理解，这有很大的差距，这会导致广告药物反应或药物 效率低下。我们研究的长期目标是开发方法，以更好地预测个体中高度可变的CYP2D6活性。我们的假设是，遗传和环境因子调节特定转录因子的表达/活性，小型异二聚体伴侣（SHP），进而改变CYP2D6的表达。我们进一步假设这部分是导致CYP2D6表达中个体差异的原因。我们的假设是基于我们最近在CYP2D6人性化的转基因（TG-CYP2D6）小鼠中抑制CYP2D6表达的发现。此外，化合物增强了SHP表达抑制肝CYP2D6表达，SHP和CYP2D6表达在人肝组织中呈负相关。这些数据强烈表明SHP在确定CYP2D6表达中起关键作用，并且SHP的差异表达导致CYP2D6变异性。为了检验我们的假设，我们提出了以下特定目的：（1）确定SHP调节剂在TG-CYP2D6小鼠中引起CYP2D6表达的改变程度，以及（2）确定解释人肝组织中CYP2D6变异性的SHP调节剂。当前预测CYP2D6活性的努力仅取决于CYP2D6基因型，并且无法解释大多数人群中CYP2D6的可变性。预计拟议的工作将揭示以前未知的CYP2D6变异性贡献者（即控制SHP表达和/或活性的外在和遗传因素），从而提高了预测CYP2D6活性的能力。我们认为，这最终将导致制定策略，以最大程度地减少CYP2D6底物过量和剂量不足的危险风险。