Keto Amphetamine Toxicity-Focus on the Redox Reactivity of the Cathinone Designer Drug Mephedrone
Keto Amphetamine Toxicity-Focus on the Redox Reactivity of the Cathinone Designer Drug Mephedrone
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DOI：
10.1093/toxsci/kfu108
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发表时间：
2014-09-01
影响因子：
3.8
通讯作者：
Kankuri, Esko
中科院分区：
文献类型：
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作者：
den Hollander, Bjornar;Sundstrom, Mira;Kankuri, Esko
甲氧麻黄酮(4-甲基甲卡西酮，4-MMC)等β-酮基苯丙胺(卡西酮，β-KA)设计药物的结构与甲基苯丙胺(甲基苯丙胺)等苯丙胺有很大程度的结构相似性。然而，这些物质是否也具有非酮基苯丙胺的潜在神经毒性特性，或者可能涉及的机制，目前知之甚少。在这里，我们使用乳酸脱氢酶试验来评估β-KA对SH-SY5Y细胞的细胞毒性，使用灵敏的氧化还原指示剂2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2，4-disulfophenyl)-2H-tetrazolium(WST-1)来评估一系列β-KA和非酮基苯丙胺的氧化还原潜力，并使用超高效液相色谱/高分辨率飞行时间质谱仪来探索4-MMC对蛋白质加合物形成和线粒体呼吸链的影响。我们发现用β-KAS治疗可以增加乳酸脱氢酶的释放。此外，我们证明，即使在生理pH下，与非酮类似物相比，β-KA在电子受体存在的情况下也是有效的和选择性的。提高pH值(范围7.6-8.0)可使反应活性提高6倍以上。我们没有发现蛋白质加合物形成的证据，这表明反应活性是由于β-KA直接电子转移所致。最后，我们发现4-MMC和冰毒对呼吸链的影响不同。我们的结果表明，4-MMC等β-KA在体外具有细胞毒作用。此外，在接受电子的氧化还原伙伴的存在下，β-KAs的酮部分对于pH依赖的氧化还原反应是至关重要的。需要进一步的工作来确定β-KA氧化还原特性的重要性及其在体内的潜在毒理学重要性。
The beta-keto amphetamine (cathinone, beta-KA) designer drugs such as mephedrone (4-methylmethcathinone, 4-MMC) show a large degree of structural similarity to amphetamines like methamphetamine (METH). However, little is currently known about whether these substances also share the potential neurotoxic properties of their non-keto amphetamine counterparts, or what mechanisms could be involved. Here, we evaluate the cytotoxicity of beta-KAs in SH-SY5Y cells using lactate dehydrogenase (LDH) assays, assess the redox potential of a range of beta-KAs and non-keto amphetamines using the sensitive redox indicator 2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1), and explore the effect of 4-MMC on the formation of protein adducts using ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) and on the mitochondrial respiratory chain using high-resolution respirometry. We show that treatment with beta-KAs increases LDH release. Further, we demonstrate that even under physiological pH, beta-KAs are effective and selective-as compared with their non-keto analogues-reductants in the presence of electron acceptors. Increased pH (range 7.6-8.0) greatly enhanced the reactivity up to sixfold. We found no evidence of protein adduct formation, suggesting the reactivity is due to direct electron transfer by the beta-KAs. Finally, we show that 4-MMC and METH produce dissimilar effects on the respiratory chain. Our results indicate that beta-KAs such as 4-MMC possess cytotoxic properties in vitro. Furthermore, in the presence of an electron-accepting redox partner, the ketone moiety of beta-KAs is vital for pH-dependent redox reactivity. Further work is needed to establish the importance of beta-KA redox properties and its potential toxicological importance in vivo.