精神活性物质对人类野生型和多态性 T356M 多巴胺转运体（DAT）的差异影响。
Differential effects of psychoactive substances on human wildtype and polymorphic T356M dopamine transporters (DAT).
机构信息
Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands; Dutch Poisons Information Center (DPIC), University Medical Center Utrecht, Utrecht University, P.O. Box 85.500, NL-3508, GA, Utrecht, the Netherlands.
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA, Nijmegen, the Netherlands.
出版信息
Toxicology. 2019 Jun 15;422:69-75. doi: 10.1016/j.tox.2019.04.012. Epub 2019 Apr 19.
Many psychoactive substances affect the human dopamine (DA) reuptake transporter (hDAT). Polymorphisms in the encoding gene could affect the functionality of the transporter and consequently alter effects of psychotropic and recreational drugs. Recently, a T356 M single nucleotide polymorphism in the human SLC6A3 gene was described, which resulted in functional impairments of DA uptake. Therefore, we investigated the effects of 10 psychoactive substances (0.01-1000 μM)) on DA uptake in human embryonic kidney (HEK) 293 cells transiently overexpressing wildtype (WT) or T356 M hDAT. Our data shows that T356 M hDAT has a 3 times lower V and a 3 times higher K compared to WT hDAT. Additionally, all psychoactive substances inhibited DA uptake by T356 M and WT hDAT. The DA reuptake inhibitors (methylphenidate, cocaine, and bupropion) inhibited DA uptake by WT hDAT most potently, followed by amphetamine-type stimulants [4-fluoroamphetamine (4-FA), amphetamine and MDMA], selective serotonin reuptake inhibitors (SSRI; fluoxetine and citalopram) and arylcyclohexylamines [methoxetamine (MXE) and ketamine]. Compared to DA uptake by WT hDAT, bupropion, methylphenidate, cocaine, and MXE less potently inhibited DA uptake by T356 M hDAT, while citalopram more potently inhibited uptake. The differences in IC values between T356 M and WT hDAT were considerable (3-45 fold). As such, the presence of this polymorphism could affect treatment efficiency with these substances as well as susceptibly for toxicity and addiction for individuals carrying this polymorphism.
许多精神活性物质会影响人体多巴胺（DA）再摄取转运蛋白（hDAT）。编码基因中的多态性可能会影响转运蛋白的功能，从而改变精神药物和娱乐性药物的作用。最近，人类 SLC6A3 基因中的 T356M 单核苷酸多态性被描述为导致 DA 摄取功能受损。因此，我们研究了 10 种精神活性物质（0.01-1000μM）对瞬时过表达野生型（WT）或 T356M hDAT 的人胚肾（HEK）293 细胞中 DA 摄取的影响。我们的数据表明，T356M hDAT 的 V 比 WT hDAT 低 3 倍，K 比 WT hDAT 高 3 倍。此外，所有精神活性物质均抑制 WT 和 T356M hDAT 的 DA 摄取。DA 再摄取抑制剂（哌甲酯、可卡因和安非他命）对 WT hDAT 的 DA 摄取抑制作用最强，其次是安非他命类兴奋剂[4-氟安非他命（4-FA）、安非他命和 MDMA]、选择性 5-羟色胺再摄取抑制剂（SSRIs；氟西汀和西酞普兰）和芳基环己基胺[甲氧基乙胺（MXE）和氯胺酮]。与 WT hDAT 的 DA 摄取相比，安非他命、哌甲酯、可卡因和 MXE 对 T356M hDAT 的 DA 摄取抑制作用较弱，而西酞普兰的抑制作用较强。T356M 和 WT hDAT 之间的 IC 值差异很大（3-45 倍）。因此，这种多态性的存在可能会影响携带这种多态性的个体对这些物质的治疗效果以及对毒性和成瘾的易感性。
Zotero 插件