CYP2D6 Genotype and Cognitive Deficits in Methamphetamine Users with/without HIV

患有/不患有艾滋病毒的甲基苯丙胺使用者的 CYP2D6 基因型和认知缺陷

基本信息

批准号：
8650822
负责人：
MARIANA CHERNER
金额：
$ 37.4万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8650822
关键词：
Address Affect Alcohol or Other Drugs use Amines Anabolism Anti-Retroviral Agents Antidepressive Agents Anxiety Brain Brain Injuries Clinical Clinical Data Code Cognition Cognitive Cognitive deficits Collection Communicable Diseases Comorbidity Consumption Cytochrome P-450 CYP2D6 Cytochrome a Cytochromes Data Data Analyses Dopamine Drug usage Enzymes Equilibrium Frequencies Functional disorder Funding Future Genes Genetic Genetic Polymorphism Genotype HIV HIV Infections Hepatitis C Hepatitis C virus Impairment Impulsivity Individual Injection of therapeutic agent Injury Intervention Investigation Investments Lead Link Literature Liver diseases Medicine Mental Depression Metabolic Metabolic Biotransformation Metabolism Methamphetamine National Institute of Drug Abuse National Institute of Mental Health Neurocognitive Neurocognitive Deficit Neurotransmitters Outcome Participant Patients Persons Phenotype Play Psychostimulant dependence Psychotropic Drugs Regimen Reporting Resources Risk Ritonavir Role Sample Size Sampling Selective Serotonin Reuptake Inhibitor Serotonin Severities Single Nucleotide Polymorphism Sorting - Cell Movement Variant Work addiction drug metabolism gene interaction information gathering inhibitor/antagonist methamphetamine exposure nerve injury neuropsychological public health relevance

项目摘要

DESCRIPTION (provided by applicant): Although cytochrome P450-2D6 (CYP2D6) is the primary enzyme responsible for methamphetamine (meth) metabolism, no work has been conducted outside of our group on its role in meth-related brain dysfunction. Our preliminary data with a small sample suggests that genetic differences coding for the activity of CYP2D6 are associated with differential vulnerability to neurocognitive problems in meth users. Individuals with genotypes corresponding to diminished metabolism seem to incur less neuropsychological impairment than those with normal metabolism. This is an intriguing finding, as it implicates the metabolic products of methamphetamine in brain injury. It also suggests that certain individuals are at increased risk of meth-related brain problems. Our group has described additive negative effects of meth, HIV, and hepatitis C (HCV) on brain function. There is evidence that liver disease, such as in HCV, as well as HIV, may alter CYP2D6 activity such that the genotype does not always correspond with the actual metabolic activity phenotype. Additionally, serotonin reuptake inhibitors for depression, which are very widely prescribed, are also substrates and inhibitors of CYP2D6 and thus may affect methamphetamine metabolism if taken concurrently. Finally, the antiretroviral ritonavir, used to boost the majority of cART regimens, is also a CYP2D6 inhibitor, and there are reports in the literature of prolonged psychoactive drug effects in HIV patients taking this medicine. As a first step in understanding whether CYP2D6 variants truly contribute to brain dysfunction associated with meth, we propose to generate CYP2D6 genotypes to replicate the small study referenced above with a large sample, and perform "deep" data analysis to understand the complexities that may mitigate the relationship between drug metabolism and cognitive outcomes. To do this, we propose to leverage an incredible resource in the form of stored samples that are accompanied by extensive clinical characterization collected from a number of projects funded by NIDA and NIMH over the past 15 years, which likely constitute the largest collection of well- characterized methamphetamine dependent cases available anywhere. Findings could lead to pharmacologic interventions to reduce brain injury as well as inform treatment choices for meth users with HIV or HCV infection.

描述（由申请人提供）：虽然细胞色素 P450-2D6 (CYP2D6) 是负责甲基苯丙胺 (meth) 代谢的主要酶，但我们小组之外尚未对其在甲基苯丙胺相关脑功能障碍中的作用进行研究。我们的小样本初步数据表明，编码 CYP2D6 活性的遗传差异与冰毒使用者神经认知问题的不同脆弱性有关。与新陈代谢正常的人相比，具有与新陈代谢减弱相对应的基因型的个体似乎遭受更少的神经心理损伤。这是一个有趣的发现，因为它表明甲基苯丙胺的代谢产物与脑损伤有关。它还表明某些人患与冰毒相关的大脑问题的风险增加。我们的小组描述了冰毒、艾滋病毒和丙型肝炎 (HCV) 对大脑功能的附加负面影响。有证据表明，肝病（例如 HCV 和 HIV）可能会改变 CYP2D6 活性，从而导致基因型并不总是与实际代谢活动表型相对应。此外，广泛使用的治疗抑郁症的血清素再摄取抑制剂也是 CYP2D6 的底物和抑制剂，因此如果同时服用，可能会影响甲基苯丙胺的代谢。最后，用于增强大多数 cART 治疗方案的抗逆转录病毒利托那韦也是一种 CYP2D6 抑制剂，文献中有报道称，服用该药的 HIV 患者会出现长期的精神药物效应。作为了解 CYP2D6 变体是否真正导致与冰毒相关的脑功能障碍的第一步，我们建议生成 CYP2D6 基因型，以用大样本复制上述小型研究，并进行“深度”数据分析以了解可能减轻影响的复杂性药物代谢与认知结果之间的关系。为此，我们建议利用存储样本形式的令人难以置信的资源，这些样本伴随着从过去 15 年 NIDA 和 NIMH 资助的许多项目中收集的广泛临床特征，这些项目可能构成了最大的良好收集。随处可见的特征性甲基苯丙胺依赖病例。研究结果可能会导致药物干预，以减少脑损伤，并为感染 HIV 或 HCV 的冰毒使用者提供治疗选择。