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(申请人提供)：非故意的药物过量或不足是一个巨大的临床问题。CYP2D6介导的药物代谢的巨大个体间变异性是造成这一问题的关键因素，因为它导致了对给定剂量的CYP2D6底物做出反应的不良药物结果的不可预测的发生。已知的是，CYP2D6的遗传多态部分解释了变异，特别是对于代谢不良的表型；然而，它们不能解释剩余群体中的大部分变异(~90%)。越来越多的证据有力地表明，在转录水平上对细胞色素P450-2D6的差异调控在决定细胞色素P450-2D6介导的药物代谢中起着关键作用。在健康的人肝组织中，CYP2D6的mRNA水平与该酶的活性高度相关。这种相关性水平类似于CYP3A4基因，该基因的表达主要在转录水平上受到控制。尽管有这些证据，但人们对控制CYP2D6转录的因素知之甚少。因此，我们对导致药物不良反应或药物的个体间差异的理解存在很大差距。 效果不佳。我们研究的长期目标是开发更好地预测个体中高度可变的CYP2D6活性的方法。我们的假设是，遗传和环境因素调节一种特定的转录因子-小异源二聚体伙伴(SHP)的表达/活性，这反过来又改变了CYP2D6的表达。我们进一步假设，这在一定程度上是造成CYP2D6表达的个体间差异的原因。我们的假设是基于我们最近在CYP2D6人源化转基因(TG-CYP2D6)小鼠中发现的SHP抑制CYP2D6表达的结果。此外，增强SHP表达的化合物抑制了肝脏中CYP2D6的表达，并且SHP和CYP2D6在人肝组织中的表达呈负相关。这些数据有力地表明，SHP在调节CYP2D6的表达中起着关键作用，并且SHP的差异表达导致了CYP2D6的变异。为了验证我们的假设，我们提出了以下具体目标：(1)确定SHP调节剂在多大程度上导致TG-CYP2D6小鼠CYP2D6表达的变化，以及(2)确定SHP调节剂可以解释人类肝脏组织中CYP2D6的变异性。目前预测细胞色素P450 2D6活性的努力完全依赖于细胞色素P450 2D6基因分型，无法解释大多数人群中的细胞色素2D6基因变异。这项拟议的工作有望揭示以前未知的导致CYP2D6可变性的因素(即控制SHP表达和/或活性的外部和遗传因素)，从而提高预测CYP2D6活性的能力。我们相信，这最终将导致制定战略，最大限度地减少危险药物过量和不足使用CYP2D6底物的风险。