Genetics of Monooxygenase Activity & Methamphetamine-Related Brain Injury in HIV

描述（由申请人提供）：甲基苯丙胺（METH）依赖性中出现的认知和运动障碍通常与药物使用参数无关，如禁欲时间、终生消费、慢性、递送方式等。这表明可能存在对METH神经毒性作用易感性的个体差异。一些甲基苯丙胺使用者出现NP损伤，而其他有类似药物暴露的人则没有，这一概念表明，甲基苯丙胺神经毒性作用的脆弱性可能存在个体差异。虽然需要探索一些候选机制，但对甲氧亚甲基效应的不同脆弱性的一个可能来源可能是甲氧亚甲基代谢的差异。细胞色素P450- 2D 6（CYP 2D 6）和含黄素的单加氧酶-3 FMO 3参与许多精神活性物质（包括METH）的氧化代谢。两者都具有影响其酶活性的功能多态性，从而导致不同的代谢速率。我们有证据表明，与代谢效率较低的表型（中间代谢者和弱代谢者）相比，具有广泛（野生型）代谢者CYP 2D 6表型的METH依赖性研究参与者表现出认知障碍的可能性是三倍，即使所有人都具有可比的METH暴露参数。这暗示代谢物的形成，可能高于母体物质本身，是甲基神经毒性的来源。因此，我们建议检查CYP 2D 6和FMO 3基因型和神经病理学变化的脑组织中观察到的METH依赖受试者死于艾滋病之间的关系。我们建议应用有效的体视学分析方法来检测已知受METH影响的大脑区域中突触树突简化的证据，以及测量氧化应激的证据。我们将利用国家神经艾滋病组织联盟的脑组织库，这些脑组织来自接受了广泛的死前神经医学和神经行为表征的患者。我们预测，受试者的基因型对应于更高水平的METH代谢将有更高水平的神经认知功能障碍在生活中，以及死后观察到的神经病理学变化的证据更大。据我们所知，这是第一次进行这种类型的调查。收集的数据，结合我们的初步临床数据，然后将用于支持应用程序的一个更大的研究的遗传决定因素的脆弱性，以甲基苯丙胺相关的脑损伤。 公共卫生相关性：甲基苯丙胺（METH）依赖中出现的神经行为缺陷往往与药物使用参数无关，这表明可能存在对METH神经毒性作用易感性的个体差异。我们建议检查甲基代谢的细胞色素P450- 2D 6（CYP 2D 6）和黄素含单加氧酶-3（FMO 3），认知障碍，死后脑损伤的证据之间的关系的遗传差异。所收集的信息可以帮助揭示由重复METH暴露引起的神经损伤的差异脆弱性机制。

DESCRIPTION (provided by applicant): Cognitive and motor impairments seen in methamphetamine (METH) dependence are often unrelated to drug use parameters such as length of abstinence, lifetime consumption, chronicity, mode of delivery, etc. This suggests the possibility of individual differences in vulnerability to the neurotoxic effects of METH. The notion that some METH users develop NP impairments, while others with similar drug exposure do not, suggests that there may be individual differences in vulnerability to the neurotoxic effects of METH. While a number of candidate mechanisms need to be explored, one possible source of differential vulnerability to METH effects may be differences in METH metabolism. Cytochrome P450-2D6 (CYP2D6) and flavin-containing monooxygenase-3 FMO3 are involved in the oxidative metabolism of a number of psychoactive substances, including METH. Both have functional polymorphisms that affect their enzymatic activity, resulting in different rates of metabolism. We have evidence that METH dependent study participants with the extensive (wildtype) metabolizer CYP2D6 phenotype were three times as likely to manifest cognitive impairments compared to those with phenotypes corresponding to lower metabolic efficiency (intermediate and poor metabolizers), even though all had comparable METH exposure parameters. This implicates metabolite formation, perhaps above the parent substance itself, as a source of METH neurotoxicity. We therefore propose to examine the relationship between CYP2D6 and FMO3 genotypes and neuropathologic changes observed in brain tissue from METH dependent subjects who died with AIDS. We propose apply well-validated methods of stereological analysis to detect evidence of synaptodendritic simplication in brain regions known to be affected by METH, as well as measure evidence of oxidative stress. We will utilize brain tissue banked at the National NeuroAIDS Tissue Consortium from patients who received extensive antemortem neuomedical and neurobehavioral characterization. We predict that subjects whose genotypes correspond to higher levels of METH metabolism will have had higher levels of neurocognitive dysfunction during life as well as greater evidence of neuropathologic changes observed postmortem. To our knowledge, this is the first investigation of this type. The data collected, combined with our preliminary clinical data, would then be used in support of an application for a larger study of genetic determinants of vulnerability to METH-related brain injury. PUBLIC HEALTH RELEVANCE: Neurobehavioral deficits seen in methamphetamine (METH) dependence are often unrelated to drug use parameters, suggesting the possibility of individual differences in vulnerability to the neurotoxic effects of METH. We propose to examine the relationship between genetic differences in METH metabolism by cytochrome P450-2D6 (CYP2D6) and flavin-containing monooxygenase-3 (FMO3), cognitive impairment, and evidence of postmortem brain injury. The information gathered can help to uncover mechanisms of differential vulnerability to neural injury caused by repeated METH exposure.