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（由申请人提供）：无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差异是造成该问题的关键因素，因为它导致对给定剂量的 CYP2D6 底物的反应中不可预测的不良药物结果的发生。众所周知，CYP2D6 的遗传多态性部分解释了这种变异性，特别是对于代谢不良表型；然而，他们无法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，CYP2D6 在转录水平上的差异调节在决定 CYP2D6 介导的药物代谢中起着关键作用。在健康的人类肝组织中，CYP2D6 的 mRNA 水平与该酶的活性高度相关。相关性水平与 CYP3A4 类似，该基因的表达主要在转录水平上受控。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不良反应的个体差异的理解存在很大差距。 无效。我们研究的长期目标是开发方法来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素调节特定转录因子小异二聚体伴侣 (SHP) 的表达/活性，从而改变 CYP2D6 表达。我们进一步假设这部分是造成 CYP2D6 表达个体间差异的原因。我们的假设基于我们最近在 CYP2D6 人源化转基因 (Tg-CYP2D6) 小鼠中的发现，即 SHP 抑制 CYP2D6 表达。此外，增强SHP表达的化合物抑制肝脏CYP2D6表达，并且SHP和CYP2D6表达在人肝组织中呈负相关。这些数据强烈表明，SHP 在调节 CYP2D6 表达中发挥关键作用，并且 SHP 的差异表达导致 CYP2D6 变异。为了检验我们的假设，我们提出以下具体目标：（1）确定 SHP 调节剂引起 Tg-CYP2D6 小鼠 CYP2D6 表达改变的程度，以及（2）识别解释人类肝组织中 CYP2D6 变异性的 SHP 调节剂。目前预测 CYP2D6 活性的努力完全依赖于 CYP2D6 基因型，无法解释大多数人群中 CYP2D6 的变异性。拟议的工作预计将揭示以前未知的 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），从而提高预测 CYP2D6 活性的能力。我们相信，这最终将导致制定策略，以最大限度地减少 CYP2D6 底物剂量过量和剂量不足的危险药物的风险。