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）：尽管细胞色素P450-2D6（CYP2D6）是负责甲基苯丙胺（METH）代谢的主要酶，但在我们组以外没有对其在甲基相关脑功能障碍中的作用进行任何作用。我们的初步数据具有小样本，表明编码CYP2D6活性的遗传差异与甲基苯丙胺使用者中神经认知问题的差异有关。对应于代谢降低的基因型的个体似乎比正常代谢的个体造成的神经心理学障碍更少。这是一个有趣的发现，因为这意味着甲基苯丙胺在脑损伤中的代谢产物。这也表明某些人面临与甲基苯丙胺相关的大脑问题的风险增加。我们的小组描述了甲基甲醇，HIV和丙型肝炎（HCV）对脑功能的添加性负面影响。有证据表明，肝病（例如HCV和HIV）可能会改变CYP2D6活性，因此基因型并不总是与实际的代谢活性表型相对应。此外，抑郁症的血清素再摄取抑制剂（通常是规定的）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代谢。最后，用来促进大多数CART方案的抗逆转录病毒利托那韦也是CYP2D6抑制剂，在文献中有报道称，在服用这种药物的HIV患者中，延长的精神活性药物作用。作为理解CYP2D6变体是否真正导致与甲基甲基相关的大脑功能障碍的第一步，我们建议生成CYP2D6基因型，以复制上述小型研究，并使用大型样本进行了“深度”数据分析，以了解可能减轻药物代谢和认知能力之间关系的复杂性。为此，我们建议以存储样本的形式利用令人难以置信的资源，这些样本伴随着过去15年中由NIDA和NIMH资助的许多项目收集的广泛临床表征，这些项目可能构成了最大的特征性良好的甲基苯胺依赖性案例。发现可能会导致药物干预措施，以减少脑损伤，并为患有艾滋病毒或HCV感染的甲基苯丙胺使用者提供治疗选择。