Hepatic Metabolism and Susceptibility to Ecstasy Toxicity

描述（由申请人提供）：几种不良反应与使用3，4-（？）-亚甲二氧基甲基苯丙胺（MDMA; Ecketamine，XTC，E）有关，其中最令人担忧的是对多巴胺能神经递质系统的长期毒性。因此，亚甲二氧基甲基安非他明的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给药途径和频率。将MDMA或MDA直接注射到脑中不能再现外周给药后的神经毒性，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。我们（和其他人）提出，MDMA和MDA的肝脏衍生代谢物介导神经毒性。我们假设，MDA和MDMA的肝代谢产物数量较少，但具有反应性，这有助于其神经毒性，并且其中一类代谢产物来自N-甲基-？-甲基多巴胺（N-甲基-？-梅达）和？-梅达，然后用谷胱甘肽（GSH）清除邻醌。此外，由于氨基的碳原子a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，对映异构体的药理学特征不同，其相对神经毒性也不同。因此，在动物模型中，（S）-MDMA似乎是导致多巴胺能神经元变性的主要因素。由于MDMA的所有主要肝脏代谢物均保留了立体中心，因此所有代谢物均以一对非对映异构体的形式存在（GSH也含有一个手性中心）。因此，MDMA的神经毒性不仅取决于肝脏代谢，而且我们假设具有（S）-构型的代谢物比相应的（R）-非对映异构体更有效。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神经毒性易感性的重要决定因素。在人类中，负责MDMA代谢的I相（CYP 2D 6）和II相（COMT）酶具有多态性，表现出显著的个体间差异。由于对MDMA诱导的神经毒性易感性的个体间差异的因素尚不清楚，并且由于神经毒性依赖于代谢，因此我们假设MDMA的I相和II相代谢的差异调节个体对神经毒性的易感性。本申请中提出的研究旨在测试这些总体假设，并检查这些代谢物进入大脑的途径。因此，我们将检验MDMA代谢物的神经毒性具有立体选择性的假设（具体目标#1），对神经毒性的易感性受I相和II相肝脏代谢的调节（具体目标#2）并且由于神经毒性需要将水溶性代谢物摄入脑中，毒性还受脑摄取和脑输出过程之间的平衡调节（III期代谢）（具体目标#3）。总之，对MDMA相对于其神经毒性的药效学和毒代动力学知之甚少，也不了解导致个体间易感性的因素，本申请旨在解决我们所知的这些缺陷。公共卫生相关性：使用和滥用3，4-（戊）-亚甲二氧基甲基苯丙胺（MDMA; Ectomy，XTC，E）会产生一些不良影响，其中最令人担忧的是对大脑内专门细胞（称为多巴胺能神经元）的长期损害。因此，亚甲二氧基甲基安非他明的使用和滥用有可能引起重大的公共卫生问题。特别是，神经毒性的形成需要MDMA经肝脏代谢成代谢物，然后进入大脑。由于负责MDMA代谢和代谢物脑摄取的蛋白质在不同个体之间差异很大，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可能更容易受到MDMA（以及类似药物）不良影响的个体。

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).