CYP2D6 Genotype and Cognitive Deficits in Methamphetamine Users with/without HIV

描述(申请人提供)：虽然细胞色素P450-2D6(细胞色素P450-2D6)是负责甲基苯丙胺(冰毒)代谢的主要酶，但在我们小组之外还没有关于它在冰毒相关脑功能障碍中的作用的研究。我们的小样本初步数据表明，编码CYP2D6活性的遗传差异与冰毒使用者对神经认知问题的不同易感性有关。与代谢正常的人相比，具有与新陈代谢减弱相对应的基因的个体引起的神经心理损伤似乎更少。这是一项耐人寻味的发现，因为它表明甲基苯丙胺的代谢产物与脑损伤有关。它还表明，某些人患冰毒相关大脑问题的风险增加。我们小组已经描述了冰毒、艾滋病毒和丙型肝炎(丙型肝炎)对大脑功能的相加负面影响。有证据表明，肝脏疾病，如丙型肝炎病毒，以及艾滋病毒，可能会改变CYP2D6的活性，使得该基因并不总是与实际的代谢活动表型相对应。此外，治疗抑郁症的5-羟色胺再摄取抑制剂被广泛开出，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的代谢。最后，用于推动大多数CART方案的抗逆转录病毒利托那韦也是一种CYP2D6抑制剂，文献中有报道称，服用这种药物的艾滋病毒患者具有长期的精神活性药物效应。作为了解CYP2D6变异是否真的有助于与冰毒相关的脑功能障碍的第一步，我们建议生成CYP2D6基因型，以复制上面提到的大样本小规模研究，并执行“深入的”数据分析，以了解可能缓解药物代谢和认知结果之间关系的复杂性。为此，我们建议以储存样本的形式利用令人难以置信的资源，这些样本伴随着从NIDA和NIMH在过去15年资助的许多项目中收集的广泛的临床特征，这些项目可能构成了世界上最大的具有良好特征的甲基苯丙胺依赖病例的集合。这些发现可能会导致药物干预，以减少脑损伤，并为感染艾滋病毒或丙型肝炎病毒的冰毒使用者提供治疗选择的信息。

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.