Dopamine transporter and catechol-O-methyltransferase activities are required for the toxicity of 1-(3',4'-dihydroxybenzyl)-1,2,3, 4-tetrahydroisoquinoline.
Dopamine transporter and catechol-O-methyltransferase activities are required for the toxicity of 1-(3',4'-dihydroxybenzyl)-1,2,3, 4-tetrahydroisoquinoline.
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1-(3,4-二羟基苄基)-1,2,3,4-四氢异喹啉的毒性需要多巴胺转运蛋白和儿茶酚-O-甲基转移酶活性。
DOI：
10.1021/tx000047y
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发表时间：
2000
影响因子：
4.1
通讯作者：
Shigeru Ohta
中科院分区：
文献类型：
--
作者：
Hiroshi Kawai;Y. Kotake;Shigeru Ohta
1-(3',4'-二羟基苯甲基)-1,2,3,4-四氢异喹啉 [3', 4'DHBnTIQ (1)] 是一种内源性帕金森病诱导物质。它通过多巴胺转运蛋白被多巴胺能神经元吸收，抑制线粒体呼吸，并诱导小鼠帕金森病。我们合成了四种衍生物[芳香化、N-甲基化、N-甲基芳香化和O-甲基化（分别为2-5）]，并研究了1-5的细胞摄取和细胞毒性，以及1的代谢。除了O-甲基衍生物（5）外，所有衍生物都被多巴胺转运蛋白特异性摄取，但1的摄取效率最高。相对于1，氧化降低了v(max)，N-甲基化显着增加了K(m)，O-甲基化消除了摄取活性。在中脑细胞原代培养物中检查1-5的细胞毒性。化合物 1 在 100 µM 时使细胞活力降低近 80%，但其他化合物对细胞活力影响很小或没有影响。体内和体外研究表明，1 被可溶性儿茶酚-O-甲基转移酶 (COMT) 进行 O-甲基化。没有观察到1的芳构化和N-甲基化。我们发现多巴胺转运蛋白抑制剂和 COMT 抑制剂均能阻断 1 的细胞毒性，表明摄取和 O-甲基化都是神经毒性所必需的。因此，我们认为1通过多巴胺转运蛋白被摄入多巴胺能神经元，然后通过COMT转化为5，5具有细胞毒性和帕金森病诱导活性。
1-(3',4'-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline [3', 4'DHBnTIQ (1)] is an endogenous parkinsonism-inducing substance. It is taken up into dopaminergic neurons via the dopamine transporter, inhibits mitochondrial respiration, and induces parkinsonism in mice. We synthesized four derivatives [aromatized, N-methylated, N-methyl-aromatized, and O-methylated (2-5, respectively)] and studied the cellular uptake and cytotoxicity of 1-5, as well as the metabolism of 1. All except the O-methyl derivative (5) were specifically taken up by the dopamine transporter, but 1 was taken up most efficiently. Relative to 1, oxidation reduced v(max), N-methylation markedly increased K(m), and O-methylation eliminated the uptake activity. The cytotoxicity of 1-5 was examined in a mesencephalic cell primary culture. Compound 1 reduced cell viability by nearly 80% at 100 microM, but the other compounds had little or no effect on cell viability. In vivo and in vitro studies revealed that 1 was O-methylated by soluble catechol-O-methyltransferase (COMT). Aromatization and N-methylation of 1 were not observed. We found that dopamine transporter inhibitors and a COMT inhibitor each blocked the cytotoxicity of 1, indicating that uptake and O-methylation are both necessary for neurotoxicity. Thus, we consider that 1 is taken up into dopaminergic neurons via the dopamine transporter and then converted by COMT to 5, which has cytotoxic and parkinsonism-inducing activities.