Bai F, Jones D C, Lau S S, Monks T J
Center for Cellular and Molecular Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas 78712-1074, USA.
Chem Res Toxicol. 2001 Jul;14(7):863-70. doi: 10.1021/tx010011l.
Reactive metabolites play an important role in 3,4-(+/-)-methylenedioxyamphetamine (MDA) and 3,4-(+/-)-methylenedioxymethamphetamine (MDMA; ecstasy)-mediated serotonergic neurotoxicity, although the specific identity of such metabolites remains unclear. 5-(Glutathion-S-yl)-alpha-methyldopamine (5-GSyl-alpha-MeDA) is a serotonergic neurotoxicant found in the bile of MDA-treated rats. The brain uptake of 5-GSyl-alpha-MeDA is decreased by glutathione (GSH), but sharply increases in animals pretreated with acivicin, an inhibitor of gamma-glutamyl transpeptidase (gamma-GT) suggesting competition between intact 5-GSyl-alpha-MeDA and GSH for the putative GSH transporter. gamma-GT is enriched in blood-brain barrier endothelial cells and is the only enzyme known to cleave the gamma-glutamyl bond of GSH. We now show that pretreatment of rats with acivicin (18 mg/kg, ip) inhibits brain microvessel endothelial gamma-GT activity by 60%, and potentiates MDA- and MDMA-mediated depletions in serotonin (5-HT) and 5-hydroxylindole acidic acid (5-HIAA) concentrations in brain regions enriched in 5-HT nerve terminal axons (striatum, cortex, hippocampus, and hypothalamus). In addition, glial fibrillary acidic protein (GFAP) expression increases in the striatum of acivicin and MDA (10 mg/kg) treated rats, but remains unchanged in animals treated with just MDA (10 mg/kg). Inhibition of endothelial cell gamma-GT at the blood-brain barrier likely enhances the uptake into brain of thioether metabolites of MDA and MDMA, such as 5-(glutathion-S-yl)-alpha-MeDA and 2,5-bis-(glutathion-S-yl)-alpha-MeDA, by increasing the pool of thioether conjugates available for uptake via the intact GSH transporter. The data indicate that thioether metabolites of MDA and MDMA contribute to the serotonergic neurotoxicity observed following peripheral administration of these drugs.
反应性代谢产物在3,4-(±)-亚甲二氧基苯丙胺（MDA）和3,4-(±)-亚甲二氧基甲基苯丙胺（MDMA；摇头丸）介导的5-羟色胺能神经毒性中起重要作用，尽管此类代谢产物的具体身份仍不清楚。5-(谷胱甘肽-S-基)-α-甲基多巴胺（5-GSyl-α-MeDA）是在MDA处理的大鼠胆汁中发现的一种5-羟色胺能神经毒素。谷胱甘肽（GSH）可降低5-GSyl-α-MeDA的脑摄取，但在用阿西维辛预处理的动物中其摄取量急剧增加，阿西维辛是γ-谷氨酰转肽酶（γ-GT）的抑制剂，这表明完整的5-GSyl-α-MeDA与GSH之间竞争假定的GSH转运体。γ-GT在血脑屏障内皮细胞中富集，是已知唯一能裂解GSH的γ-谷氨酰键的酶。我们现在表明，用阿西维辛（18 mg/kg，腹腔注射）预处理大鼠可使脑微血管内皮γ-GT活性抑制60%，并增强MDA和MDMA介导的富含5-羟色胺能神经末梢轴突的脑区（纹状体、皮质、海马体和下丘脑）中5-羟色胺（5-HT）和5-羟吲哚乙酸（5-HIAA）浓度的降低。此外，在阿西维辛和MDA（10 mg/kg）处理的大鼠纹状体中，胶质纤维酸性蛋白（GFAP）表达增加，但仅用MDA（10 mg/kg）处理的动物中其表达保持不变。血脑屏障处内皮细胞γ-GT的抑制可能通过增加可通过完整的GSH转运体摄取的硫醚缀合物池，增强MDA和MDMA的硫醚代谢产物如5-(谷胱甘肽-S-基)-α-MeDA和2,5-双-(谷胱甘肽-S-基)-α-MeDA的脑摄取。数据表明，MDA和MDMA的硫醚代谢产物导致了这些药物外周给药后观察到的5-羟色胺能神经毒性。
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