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）：尽管细胞色素 P450-2D6 (CYP2D6) 是参与甲基苯丙胺 (meth) 代谢的主要酶，但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（在我们自己的工作之外）。我们通过小规模临床样本获得的初步数据表明，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。这一有趣的发现表明甲基苯丙胺的代谢产物与脑损伤有关。它还提出了一种方法来识别个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和艾滋病毒对大脑功能的附加负面影响。有证据表明 CYP2D6 活性可能在 HIV 中发生改变，因此基因型并不总是与实际代谢活性表型相对应。此外，一些广泛用于 HIV 患者的药物是 CYP2D6 的底物和抑制剂，因此如果同时服用可能会影响冰毒代谢。其中包括治疗抑郁症的血清素再摄取抑制剂以及抗逆转录病毒利托那韦，后者用于增强大多数 cART 治疗方案。文献中有报道称，服用利托那韦的 HIV 患者会出现长期精神活性药物效应。为了了解 CYP2D6 活性差异可能导致与冰毒相关的脑功能障碍的机制，我们建议建立一个与 HIV 背景下冰毒暴露相关的神经损伤的自然体外模型。我们将使用源自胎儿组织捐赠的人类混合神经胶质细胞培养物。因此，可以对培养物进行基因分型。我们建议用冰毒和 HIV 处理培养物，并且 (1) 测量代谢物的形成； (2)确定CYP2D6活性/代谢物量是否与细胞损伤量相关； (3) 检查这些结果如何受到培养物暴露于临床相关 CYP2D6 抑制剂（帕罗西汀和利托那韦）的影响。我们预计，具有广泛（野生型）代谢基因型的培养物将产生最大数量的冰毒代谢物，进而显示出最大程度的细胞损伤，其次是中间代谢基因，然后是弱代谢基因。在前期工作中，我们已经证明了所提出的实验的各个组成部分的可行性。研究结果证实了我们早期的人体研究，并提供了艾滋病毒背景下冰毒相关损伤的机制。结果可能会导致药物干预措施的开发，以减少脑损伤，并为感染艾滋病毒的冰毒使用者提供治疗选择。