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: 7688583
• 负责人: TERRENCE J. MONKS
• 金额: $ 33.4万
• 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/7688583
• 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（由适用提供）：使用3,4-（�） - 甲基二甲基甲基苯丙胺（MDMA；摇头丸，XTC，e）的几种不利影响，最担心的是对Seratononeragic Neurotansmitter系统的长期毒性。因此，MDMA使用和滥用有可能引起重大的公共卫生问题。 MDMA的神经毒性作用取决于药物给药的途径和频率。直接注射MDMA或MDA向大脑注射，无法在外周施用后再现神经毒性，这表明母体苯丙胺不太可能完全负责神经毒性。我们（和其他人）提出，MDMA和MDA的肝衍生代谢产物介导神经毒性。我们假设MDA和MDMA的定量较小但反应性的肝代谢产物有助于它们的神经毒性，并且一种这样的代谢产物是由N-甲基 - ？ - 甲基甲基胺（N-甲基 - ？ - meda- meda）和-Meda的氧化而产生的。此外，由于到胺基的碳原子A代表一个立体中心，因此MDMA可以存在于两个不同的三维镜像结构或对映异构体中：（R）-MDMA和（S）-MDMA。实际上，对映异构体的药物特征和相对神经毒性也有所不同。在动物模型中，（s）-MDMA似乎是导致血清能神经元退化的主要因素。由于MDMA的所有主要肝素代谢产物都保留了立体源性中心，因此所有代谢物都作为一对映异构体存在（GSH还包含手性中心）。因此，MDMA的神经毒性不仅取决于肝素代谢，而且我们假设拥有（S）配置的代谢产物比相应的（R） - 二甲状腺素异构体更具有潜力。由于代谢对于神经毒性的表达是必要的，因此MDMA的I期（P450）和II期（COMT）代谢的差异将是个体对MDMA神经毒性敏感性的重要决定剂。在人类中，负责MDMA代谢的I期（CYP2D6）和II期（COMT）酶是多态性的，表现出显着的个体间差异。由于尚不清楚导致MDMA诱导神经毒性敏感性的个体易变性的因素，并且神经毒性取决于代谢，因此我们假设MDMA的I阶段和II期II期代谢的差异调节了个体易感性的神经毒性。本应用中提出的研究旨在检验这些总体假设，并检查这种代谢物可以进入大脑的途径。因此，我们将检验以下假设：MDMA代谢物的神经毒性是立体选择性的（特定目的＃1），即神经毒性的易感性受到I期和II期肝代谢2的易感性（特定的目标＃2）（特定的目标＃2），并且因为神经毒性的脑含量是脑部典型的毒性，其脑介导性是脑毒性的毒性，是脑毒性的毒性，是对水的毒性的毒性，是水的毒性，毒性是型毒性的毒性，是毒性的毒性，毒性是毒性的毒性。过程（第三阶段代谢）（特定目的＃3）。总而言之，对于MDMA的神经毒性，对MDMA的药物型脱骨动力学和有毒动力学知之甚少，也不了解导致个人间敏感性的因素，并且该应用旨在解决我们所知的这些缺陷。公共卫生相关性：几种不利影响与3,4-（） - 甲基二甲基甲基苯丙胺（MDMA；摇头丸，XTC，e）的使用和滥用有关，最担心的是对大脑内部专业细胞的长期损害，称为血清素氧神经元。因此，MDMA使用和滥用有可能引起重大的公共卫生问题。特别是，神经毒性的发展需要肝脏代谢成MDMA的代谢，该代谢物随后进入大脑。由于负责MDMA代谢的蛋白质和代谢产物的大脑摄取均在不同个体之间仔细差异，因此了解这些不同过程对MDMA神经毒性的相对贡献，有助于我们确定那些可能对MDMA不良影响和可能类似药物（可能与类似药物）更容易敏感的个体。