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

描述（由申请人提供）：尽管细胞色素P450- 2D 6（CYP 2D 6）是负责甲基苯丙胺（冰毒）代谢的主要酶，但在我们小组之外尚未对其在冰毒相关脑功能障碍中的作用进行研究。我们的小样本初步数据表明，编码CYP 2D 6活性的遗传差异与冰毒使用者神经认知问题的差异脆弱性有关。与代谢正常的个体相比，具有代谢减少基因型的个体似乎较少发生神经心理学损害。这是一个有趣的发现，因为它暗示了脑损伤中甲基苯丙胺的代谢产物。它还表明，某些人患与冰毒有关的大脑问题的风险增加。我们的研究小组已经描述了冰毒、艾滋病病毒和丙型肝炎病毒（HCV）对大脑功能的附加负面影响。有证据表明，肝脏疾病（如HCV和HIV）可能会改变CYP 2D 6活性，使得基因型并不总是与实际代谢活性表型相对应。此外，用于抑郁症的5-羟色胺再摄取抑制剂也是CYP 2D 6的底物和抑制剂，如果同时服用，可能会影响甲基苯丙胺的代谢。最后，用于加强大多数cART方案的抗逆转录病毒利托那韦也是一种CYP 2D 6抑制剂，文献中有报告称，服用这种药物的HIV患者的精神活性药物作用延长。作为了解CYP 2D 6变体是否真的导致与冰毒相关的脑功能障碍的第一步，我们建议生成CYP 2D 6基因型，以大样本复制上述小规模研究，并进行“深入”数据分析，以了解可能减轻药物代谢和认知结果之间关系的复杂性。为了做到这一点，我们建议利用一个令人难以置信的资源，以存储样本的形式，伴随着广泛的临床表征，这些临床表征是从NIDA和NIMH在过去15年资助的一些项目中收集的，这些项目可能构成了任何地方都可以获得的最大的特征良好的甲基苯丙胺依赖病例的集合。研究结果可能导致药物干预，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。

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.