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首页> 外文期刊>Archives of Toxicology >The mixture of 'ecstasy' and its metabolites is toxic to human SH-SY5Y differentiated cells at in vivo relevant concentrations
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The mixture of 'ecstasy' and its metabolites is toxic to human SH-SY5Y differentiated cells at in vivo relevant concentrations

机译：摇头丸及其代谢产物的混合物在体内相关浓度下对人SH-SY5Y分化细胞有毒

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The neurotoxicity of "ecstasy" (3,4- methylenedioxymethamphetamine, MDMA) is thought to involve hepatic metabolism, though its real contribution is not completely understood. Most in vitro neurotoxicity studies concern isolated exposures of MDMA or its metabolites, at high concentrations, not considering their mixture, as expected in vivo. Therefore, our postulate is that combined deleterious effects of MDMA and its metabolites, at low micromolar concentrations that may be attained into the brain, may elicit neurotoxicity. Using human SH-SY5Y differentiated cells as dopaminergic neuronal model, we studied the neurotoxicity of MDMA and its MDMA metabolites α-methyldopamine and N-methyl-α-methyldopamine and their correspondent glutathione and N-acetylcysteine monoconjugates, under isolated exposure and as a mixture, at normothermic or hyperthermic conditions. The results showed that the mixture of MDMA and its metabolites was toxic to SH-SY5Y differentiated cells, an effect potentiated by hyperthermia and prevented by N-acetylcysteine. As a mixture, MDMA and its metabolites presented a different toxicity profile, compared to each compound alone, even at equimolar concentrations. Caspase 3 activation, increased reactive oxygen species production, and intracellular Ca2+ raises were implicated in the toxic effect. The mixture increased intracellular glutathione levels by increasing its de novo synthesis. In conclusion, this study demonstrated, for the first time, that the mixture of MDMA and its metabolites, at low micromolar concentrations, which represents a more realistic approach of the in vivo scenario, elicited toxicity to human SH-SY5Y differentiated cells, thus constituting a new insight into the context of MDMA-related neurotoxicity.
机译：尽管“摇头丸”（3，4-亚甲二氧基甲基苯丙胺，MDMA）的神经毒性涉及肝脏代谢，但其真正的作用尚未得到完全了解。大多数体外神经毒性研究都关注高浓度MDMA或其代谢产物的单独暴露，而不考虑体内预期的混合物。因此，我们的假设是，在低微摩尔浓度下，脑中可能存在的MDMA及其代谢产物的综合有害作用可能引起神经毒性。使用人类SH-SY5Y分化细胞作为多巴胺能神经元模型，我们研究了MDMA及其MDMA代谢产物α-甲基多巴胺和N-甲基-α-甲基多巴胺及其对应的谷胱甘肽和N-乙酰半胱氨酸单缀合物的神经毒性，在单独的暴露下和混合在常温或高温条件下。结果表明，MDMA及其代谢产物的混合物对SH-SY5Y分化的细胞有毒，高热可增强这种作用，而N-乙酰半胱氨酸可阻止这种作用。与单独的每种化合物相比，即使在等摩尔浓度下，作为混合物，MDMA及其代谢产物也呈现出不同的毒性。 Caspase 3的活化，活性氧的产生增加以及细胞内Ca2 +的升高都与毒性作用有关。该混合物通过增加其从头合成来增加细胞内谷胱甘肽水平。总之，这项研究首次证明，低微摩尔浓度的MDMA及其代谢物的混合物代表了一种更现实的体内方法，对人SH-SY5Y分化细胞产生了毒性，从而构成与MDMA相关的神经毒性相关的新见解。

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