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

描述(由申请人提供)：甲基苯丙胺(冰毒)依赖引起的认知和运动障碍通常与药物使用参数无关，如戒毒时间、终生消耗量、慢性病、服药方式等。这表明，对冰毒神经毒性影响的易感性可能存在个体差异。一些冰毒使用者出现NP损害，而其他有类似药物暴露的人则不会，这一概念表明，对冰毒神经毒性影响的易感性可能存在个体差异。虽然需要探索一些候选机制，但对冰毒效应的不同脆弱性的一个可能来源可能是冰毒代谢的差异。细胞色素P450-2D6和含有黄素的单加氧酶-3 FMO3参与了包括冰毒在内的许多精神活性物质的氧化代谢。两者都有影响其酶活性的功能多态，导致不同的新陈代谢速度。我们有证据表明，具有广泛(野生型)代谢物CYP2D6表型的冰毒依赖研究参与者出现认知障碍的可能性是那些具有较低代谢效率的表型(中等代谢物和较差代谢物)的参与者的三倍，即使所有人都有类似的冰毒暴露参数。这意味着代谢物的形成，可能高于母体物质本身，作为冰毒神经毒性的来源。因此，我们建议对死于艾滋病的冰毒依赖受试者的脑组织中观察到的神经病理改变与CYP2D6和FMO3基因之间的关系进行研究。我们建议应用经过验证的体视学分析方法来检测已知受冰毒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储存的脑组织，这些脑组织来自于接受了广泛的生前神经医学和神经行为特征鉴定的患者。我们预测，其基因类型与较高水平的冰毒代谢相对应的受试者，在一生中将有更高水平的神经认知功能障碍，以及更多死后观察到的神经病理变化的证据。据我们所知，这是第一次进行这类调查。收集的数据，结合我们的初步临床数据，将用于支持对冰毒相关脑损伤易感性的遗传决定因素进行更大规模研究的申请。 公共卫生相关性：甲基苯丙胺(冰毒)依赖导致的神经行为缺陷通常与药物使用参数无关，这表明对冰毒神经毒性影响的易感性可能存在个体差异。我们建议研究细胞色素P450-2D6(细胞色素P450-2D6)和黄素单加氧酶-3(FMO3)代谢的遗传差异与认知障碍和死后脑损伤证据之间的关系。收集到的信息有助于揭示反复接触冰毒造成神经损伤的不同脆弱性的机制。

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.