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向雄性斯普拉格-道利大鼠脑室内注射5-（谷胱甘肽-S-基）-α-甲基多巴胺后的代谢情况

Metabolism of 5-(glutathion-S-yl)-alpha-methyldopamine following intracerebroventricular administration to male Sprague-Dawley rats.

作者信息

Miller R T, Lau S S, Monks T J

机构信息

Division of Pharmacology & Toxicology, College of Pharmacy, University of Texas at Austin 78712, USA.

出版信息

Chem Res Toxicol. 1995 Jul-Aug;8(5):634-41. doi: 10.1021/tx00047a002.

DOI:10.1021/tx00047a002
PMID:7548745
Abstract

5-(Glutathion-S-yl)-alpha-methyldopamine [5-(GSyl)-alpha-MeDA] is a putative metabolite of the serotonergic neurotoxicants 3,4-(+/-)-(methylenedioxy)amphetamine and 3,4-(+/-)-(methylenedioxy)methamphetamine. Glutathione (GSH) conjugates of several polyphenols are biologically (re)active. Therefore, as part of our studies on the role of 5-(GSyl)-alpha-MeDA in MDA-mediated neurotoxicity, we determined the regional brain metabolism of 5-(GSyl)-alpha-MeDA (720 nmol) following intracerebroventricular administration to male Sprague-Dawley rats. 5-(GSyl)-alpha-MeDA was rapidly cleared from all brain regions examined, and regional differences in the distribution of gamma-glutamyl transpeptidase (gamma-GT) correlated with the formation of 5-(cystein-S-yl)-alpha-methyldopamine (5-[CYS]-alpha-MeDA). We also observed the formation of 5-(N-acetyl-L-cystein-S-yl)-alpha-MeDA (5-[NAC]-alpha-MeDA) in all brain regions, indicating that the brain has the ability to synthesize mercapturic acids. Peak concentrations of 5-(NAC)-alpha-MeDA were found in the order: hypothalamus > midbrain/diencephalon/telencephalon > pons/medulla > hippocampus > cortex > striatum. In contrast to 5-(GSyl)-alpha-MeDA and 5-(CYS)-alpha-MeDA, 5-(NAC)-alpha-MeDA was eliminated relatively slowly from the brain. Differences were also found in cystein conjugate N-acetyltransferase activity in microsomes prepared from the various brain regions, but little difference was observed in brain cytosolic N-acetyl-L-cysteine conjugate N-deacetylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

摘要

5-（谷胱甘肽-S-基）-α-甲基多巴胺[5-（GSyl）-α-MeDA]是血清素能神经毒素3,4-（±）-（亚甲二氧基）苯丙胺和3,4-（±）-（亚甲二氧基）甲基苯丙胺的一种假定代谢产物。几种多酚的谷胱甘肽（GSH）缀合物具有生物（再）活性。因此，作为我们关于5-（GSyl）-α-MeDA在MDA介导的神经毒性中作用研究的一部分，我们测定了向雄性Sprague-Dawley大鼠脑室内注射5-（GSyl）-α-MeDA（720 nmol）后脑内各区域的代谢情况。5-（GSyl）-α-MeDA从所有检测的脑区迅速清除，γ-谷氨酰转肽酶（γ-GT）分布的区域差异与5-（半胱氨酸-S-基）-α-甲基多巴胺（5-[CYS]-α-MeDA）的形成相关。我们还观察到在所有脑区均形成了5-（N-乙酰-L-半胱氨酸-S-基）-α-甲基多巴胺（5-[NAC]-α-MeDA），这表明大脑具有合成硫醚氨酸的能力。5-（NAC）-α-MeDA的峰值浓度顺序为：下丘脑＞中脑/间脑/端脑＞脑桥/延髓＞海马体＞皮质＞纹状体。与5-（GSyl）-α-MeDA和5-（CYS）-α-MeDA不同，5-（NAC）-α-MeDA从脑中清除相对较慢。在从不同脑区制备的微粒体中，半胱氨酸缀合物N-乙酰转移酶活性也存在差异，但在脑胞质N-乙酰-L-半胱氨酸缀合物N-脱乙酰酶活性方面观察到的差异较小。（摘要截短于250字）

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