Modeling Neural Injury Effects of Methamphetamine Metabolism by CYP2D6 in HIV

模拟 HIV 中 CYP2D6 甲基苯丙胺代谢的神经损伤效应

• 批准号: 8602613
• 负责人: MARIANA CHERNER
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8602613
• 关键词: Affect; Anti-Retroviral Agents; Antidepressive Agents; Brain; Brain Injuries; Caspase; Cell Culture Techniques; Characteristics; Chemosensitization; Clinical; Clinical Management; Code; Complement; Consumption; Cytochrome P-450 CYP2D6; Cytochrome a; Cytochromes; Data; Development; Enzymes; Exposure to; Fetal Tissue Donations; Functional disorder; Genetic; Genotype; HIV; HIV Infections; Human; Impairment; Individual; Injury; Intervention; Lactate Dehydrogenase; Lead; Literature; Liver; Measures; Medicine; Mental Depression; Metabolic; Metabolism; Methamphetamine; Modeling; Neurocognitive; Paroxetine; Patients; Pharmaceutical Preparations; Phenotype; Production; Prospective Studies; Psychotropic Drugs; Regimen; Reporting; Risk; Ritonavir; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Testing; Tissue Donors; Work; base; brain cell; brain tissue; cell injury; clinically relevant; fetal; in vitro Model; information gathering; inhibitor/antagonist; methamphetamine exposure; nerve injury; neuropsychological; neurotoxicity; public health relevance; research study; therapeutic target

DESCRIPTION (provided by applicant): Despite being the primary enzyme involved in methamphetamine (meth) metabolism, cytochrome P450-2D6 (CYP2D6) has not been studied (outside of our own work) with regard to its role in meth-related brain dysfunction. Our preliminary data with a small clinical sample suggest 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 intriguing finding implicates the metabolic products of methamphetamine in brain injury. It also suggests a way to identify individuals are at increased risk of meth-related brain problems. Our group has described additive negative effects of meth and HIV on brain function. There is evidence that CYP2D6 activity may be altered in HIV, such that the genotype does not always correspond with the actual metabolic activity phenotype. Additionally, there are medications that are widely prescribed to HIV patients that are substrates and inhibitors of CYP2D6 and thus may affect meth metabolism if taken concurrently. These include serotonin reuptake inhibitors for depression as well as the antiretroviral ritonavir, which is used to boost a majority of cART regimens. There are reports in the literature of prolonged psychoactive drug effects in HIV patients taking ritonavir. To understand the mechanisms by which differences in CYP2D6 activity may contribute to meth-related brain dysfunction, we propose to generate a naturalistic in vitro model of neural injury associated with meth exposure in the context of HIV. We will use human mixed neuroglial cultures derived from fetal tissue donation. As such, the cultures can be genotyped. We propose to treat the cultures with meth and HIV, and (1) measure metabolite formation; (2) determine whether CYP2D6 activity / metabolite quantities are related to amount of cellular injury; and (3) examine how these results are affected by exposure of the cultures to clinically relevant CYP2D6 inhibitors (paroxetine and ritonavir). We expect that cultures with extensive (wildtype) metabolizer genotypes will generate the largest quantities of meth metabolites and will in turn show the greatest degree of cellular injury, followed by intermediate and then poor metabolizers. In preliminary work, we have demonstrated the feasibility of the various components of the proposed experiments. Findings stand to confirm our early human studies and provide a mechanism of meth-related injury in the context of HIV. Results could lead to the development of pharmacologic interventions to reduce brain injury as well as inform treatment choices for meth users with HIV.

描述（由申请人提供）：尽管是参与甲基苯丙胺（METH）代谢的主要酶，但在我们自己的工作中的作用（在我们自己的工作之外）尚未研究细胞色素P450-2D6（CYP2D6）。我们的初步数据具有少量的临床样本，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。这个有趣的发现暗示了甲基苯丙胺在脑损伤中的代谢产物。它还提出了一种识别个人与甲基甲基相关脑部问题的风险增加的方法。我们的小组描述了甲基甲基和HIV对脑功能的添加性负面影响。有证据表明，CYP2D6活性可能会改变HIV，因此基因型并不总是与实际的代谢活性表型相对应。此外，还有一些药物为HIV患者开处方，这些药物是CYP2D6的底物和抑制剂，因此如果同时服用，可能会影响甲基代谢。其中包括抑郁症的5-羟色胺再摄取抑制剂以及抗逆转录病毒利托那韦，该抑制剂用于增强大多数CART方案。文献中有报道称，服用利托纳维尔的艾滋病毒患者长期精神活性药物作用。为了了解CYP2D6活性差异可能导致与甲基相关的脑功能障碍的机制，我们建议在HIV背景下产生与甲基甲基损伤相关的自然主义体外神经损伤模型。我们将使用源自胎儿组织捐赠的人类混合神经培养物。因此，可以将培养物进行基因分型。我们建议用甲基和艾滋病毒治疗培养物，以及（1）测量代谢产物的形成； （2）确定CYP2D6活性 /代谢物量是否与细胞损伤量有关； （3）检查这些结果如何受到培养物暴露于临床相关的CYP2D6抑制剂（Paroxetine和Ritonavir）的影响。我们预计具有广泛（WildType）代谢剂基因型的培养物将产生最大数量的甲基代谢产物，进而显示出最大程度的细胞损伤，其次是中间体和不良代谢物。在初步工作中，我们已经证明了拟议实验的各个组成部分的可行性。调查结果旨在确认我们的早期人类研究，并在HIV背景下提供与甲基相关损伤的机制。结果可能导致制定药理干预措施以减少脑损伤，并为艾滋病毒使用者提供治疗选择。