Hepatic Metabolism and Susceptibility to Ecstasy Toxicity

肝脏代谢和对摇头丸毒性的敏感性

• 批准号: 7860382
• 负责人: TERRENCE J. MONKS
• 金额: $ 33.16万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860382
• 关键词: Address; Adverse effects; Amines; Amphetamines; Animal Model; Animals; Area; Benzene; Blood - brain barrier anatomy; Brain; CYP2D1 gene; CYP2D6 gene; Carbon; Carrier Proteins; Catechol O-Methyltransferase; Catecholamines; Cells; Chemical Structure; Clinical; Cytochrome P450; Data; Deoxyepinephrine; Development; Dopamine; Endothelial Cells; Enzymes; Equilibrium; Exhibits; Female; Frequencies; Genetic; Glial Fibrillary Acidic Protein; Glutathione; Hepatic; Human; Image; In Vitro; Individual; Individual Differences; Injection of therapeutic agent; Knockout Mice; Knowledge; Laboratories; Liver; Mediating; Metabolism; Methamphetamine; Microglia; Minor; Modeling; Multidrug Resistance-Associated Proteins; Nerve; Neurons; Neurotransmitters; Organic Anion Transporters; Parents; Pathway interactions; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Positioning Attribute; Predisposition; Process; Proteins; Public Health; Quinones; Rattus; Relative (related person); Route; Serotonin; Sprague-Dawley Rats; Structure; System; Testing; Toxic effect; Toxicokinetics; Water; base; design; ecstasy; enantiomer; inhibitor/antagonist; neurotoxic; neurotoxicity; oxidation; public health relevance; response; thioether; uptake

DESCRIPTION (provided by applicant): Several adverse effects are associated with the use of 3,4-(¿)-methylenedioxymethamphetamine (MDMA; Ecstasy, XTC, E), the most worrisome of which is long-term toxicity to the serotonergic neurotransmitter system. MDMA use and abuse therefore has the potential to give rise to a major public health problem. The neurotoxic effects of MDMA are dependent on the route and frequency of drug administration. Direct injection of either MDMA or MDA into the brain fails to reproduce the neurotoxicity following peripheral administration, indicating that the parent amphetamines are unlikely to be solely responsible for the neurotoxic effect. We (and others) have proposed that liver-derived metabolites of MDMA and MDA mediate the neurotoxicity. We hypothesize that quantitatively minor, yet reactive hepatic metabolites of MDA and MDMA contribute to their neurotoxicity, and that one such class of metabolites arise from the oxidation of N-methyl-?-methyldopamine (N-methyl-?-MeDA) and ?-MeDA, followed by scavenging of the ortho-quinones with glutathione (GSH). Moreover, because the carbon atom a to the amine group represents a stereogenic center, MDMA can exist in two different three-dimensional mirror-image structures, or enantiomers: (R)-MDMA and (S)-MDMA. Indeed, the pharmacological profiles of the enantiomers differ, as does their relative neurotoxicity. Thus, in animal models, (S)-MDMA appears to be the major contributor to the degeneration of serotonergic neurons. Because all the principal hepatic metabolites of MDMA retain the stereogenic center, it follows that all of the metabolites exist as a pair of diastereoisomers (GSH also contains a chiral center). Therefore, not only is the neurotoxicity of MDMA dependent upon hepatic metabolism, but we hypothesize that metabolites possessing the (S)-configuration will be more potent than the corresponding (R)-diastereoisomers. Because metabolism is necessary for the expression of neurotoxicity, differences in the Phase I (P450) and Phase II (COMT) metabolism of MDMA will be important determinants of individual susceptibility to the neurotoxicity of MDMA. In humans, the phase I (CYP2D6) and phase II (COMT) enzymes responsible for MDMA metabolism are polymorphic, exhibiting significant inter-individual differences. Since the factors that contribute to the inter-individual variability in susceptibility to MDMA induced neurotoxicity are not known, and since neurotoxicity is dependent upon metabolism, we hypothesize that differences in the phase I and phase II metabolism of MDMA modulate individual susceptibility to neurotoxicity. Studies proposed in this application are designed to test these overall hypotheses and to examine the pathways by which such metabolites gain access to the brain. We will therefore test the hypotheses that the neurotoxicity of MDMA metabolites is stereoselective (Specific Aim #1), that susceptibility to neurotoxicity is modulated by both Phase I and Phase II hepatic metabolism (Specific Aim #2) and that because neurotoxicity requires the uptake of water soluble metabolites into brain, toxicity is also regulated by the balance between brain uptake and brain export processes (Phase III metabolism) (Specific Aim #3). In summary, little is known about the pharmacodynamics and toxicokinetics of MDMA relative to its neurotoxicity, nor of the factors that contribute to inter-individual susceptibility, and this application is designed to address these deficits in our knowledge. PUBLIC HEALTH RELEVANCE: Several adverse effects are associated with the use and abuse of 3,4-(¿)-methylenedioxymethamphetamine (MDMA; Ecstasy, XTC, E), the most worrisome of which is long-term damage to specialized cells within the brain, known as serotonergic neurons. MDMA use and abuse therefore has the potential to give rise to a major public health problem. In particular, the development of neurotoxicity requires metabolism of MDMA by the liver into a metabolite that subsequently enters the brain. Because the proteins responsible for both the metabolism of MDMA and the brain uptake of the metabolites vary considerably between different individuals, knowledge of the relative contribution of these different processes to the neurotoxicity of MDMA will assist in our ability to identify those individuals who may be more susceptible to the adverse effects of MDMA (and perhaps to similar drugs).

描述（由申请人提供）：使用 3,4-(¿)-亚甲二氧基甲基苯丙胺（MDMA；摇头丸、XTC、E）会产生一些副作用，其中最令人担忧的是对血清素神经递质系统的长期毒性因此，摇头丸的使用和滥用有可能引起重大的公共卫生问题。摇头丸的神经毒性作用取决于药物的途径和频率。直接注射到大脑中的 MDMA 或 MDA 无法在外周给药后重现神经毒性，这表明母体安非他明不太可能是神经毒性作用的唯一原因。 MDMA 和 MDA 介导神经毒性，我们发现 MDA 和 MDMA 的数量较少但反应性的肝脏代谢物会导致其神经毒性，并且此类代谢物是由氧化产生的。 N-甲基-α-甲基多巴胺（N-甲基-α-MeDA）和α-MeDA，然后用谷胱甘肽（GSH）清除邻醌。此外，因为胺基的碳原子代表立体中心。 ，MDMA 可以以两种不同的三维镜像结构或对映体存在：(R)-MDMA 和 (S)-MDMA 事实上，对映体的药理学特征不同，因此，在动物模型中，(S)-MDMA 似乎是导致血清素能神经元退化的主要因素，因为 MDMA 的所有主要肝脏代谢物都保留了立体中心，因此所有代谢物都保留了立体中心。作为一对非对映异构体存在（GSH 也含有手性中心），因此，MDMA 的神经毒性不仅取决于肝脏代谢，而且我们捕获了具有以下特征的代谢物。 (S)-构型比相应的(R)-非对映异构体更有效，因为代谢对于神经毒性的表达是必要的，MDMA I 期 (P450) 和 II 期 (COMT) 代谢的差异将是重要的决定因素。个体对 MDMA 神经毒性的易感性 在人类中，负责 MDMA 代谢的 I 相 (CYP2D6) 和 II 相 (COMT) 酶具有多态性，表现出显着的个体间差异。由于导致 MDMA 诱导的神经毒性易感性存在个体间差异的因素尚不清楚，而且神经毒性取决于代谢，因此我们研究了 MDMA I 期和 II 期代谢的差异调节个体对 MDMA 的易感性。神经毒性 本申请中提出的研究旨在测试这些总体假设并检查此类代谢物进入大脑的途径，因此我们将测试 MDMA 代谢物的神经毒性的假设。立体选择性（具体目标 #1），对神经毒性的敏感性受到 I 期和 II 期肝脏代谢（具体目标 #2）的调节，并且由于神经毒性需要将水溶性代谢物摄取到大脑中，因此毒性也受到平衡的调节大脑摄取和大脑输出过程（第三阶段代谢）之间的关系（具体目标#3） 总之，人们对 MDMA 的药效学和毒代动力学知之甚少。神经毒性，也不是导致个体间易感性的因素，本申请旨在解决我们知识中的这些缺陷： 一些不良反应与 3,4-(¿ )-亚甲二氧基甲基苯丙胺（MDMA；摇头丸，XTC，E），其中最令人担忧的是对大脑内特殊细胞（称为血清素神经元）的长期损害，因此 MDMA 的使用和滥用有可能引起公众的关注。特别是，神经毒性的发生需要肝脏将 MDMA 代谢成代谢物，然后进入大脑，因为蛋白质负责 MDMA 和代谢物的代谢。不同个体的大脑对代谢物的吸收差异很大，了解这些不同过程对 MDMA 神经毒性的相对贡献将有助于我们识别那些可能更容易受到 MDMA 不利影响的个体（或许还有类似的副作用）。药物）。