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首页> 外文期刊>Toxicology and Applied Pharmacology >S-(+)-Pentedrone and R-(+)-methylone as the most oxidative and cytotoxic enantiomers to dopaminergic SH-SY5Y cells: Role of MRP1 and P-gp in cathinones enantioselectivity
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S-(+)-Pentedrone and R-(+)-methylone as the most oxidative and cytotoxic enantiomers to dopaminergic SH-SY5Y cells: Role of MRP1 and P-gp in cathinones enantioselectivity

机译：S - （+） - 戊酮和R - （+） - 作为多巴胺能Sh-Sy5Y细胞的最氧化和细胞毒性对映体的甲基：MRP1和P-GP在阴茎对映选择性中的作用

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Cathinone derivatives are the most representative group within new drugs market, which have been described as neurotoxic. Since cathinones, as pentedrone and methylone, are available as racemates, it is our aim to study the neuronal cytotoxicity induced by each enantiomer. Therefore, a dopaminergic SH-SY5Y cell line was used to evaluate the hypothesis of enantioselectivity of pentedrone and methylone enantiomers on cytotoxicity, oxidative stress, and membrane efflux transport (confirmed by in silico studies). Our study demonstrated enantioselectivity of these cathinones, being the S-(+)-pentedrone and R-(+)-methylone the most oxidative enantiomers and also the most cytotoxic, suggesting the oxidative stress as main cytotoxic mechanism, as previously described in in vitro studies. Additionally, the efflux transporter multidrug resistance associated protein 1 (MRP1) seems to play, together with GSH, a selective protective role against the cytotoxicity induced by R-(-)-pentedrone enantiomer. It was also observed an enantioselectivity in the binding to P-glycoprotein (P-gp), another efflux protein, being the R-(-)-pentedrone and S-(-)-methylone the most transported enantiomeric compounds. These results were confirmed, in silico, by docking studies, revealing that R-(-)-pentedrone is the enantiomer with highest affinity to MRP1 and S-(-)-methylone and R-(-)-pentedrone are the enantiomers with highest affinity to P-gp. In conclusion, our data demonstrated that pentedrone and methylone present enantioselectivity in their cytotoxicity, which seems to involve different oxidative reactivity as well as different affinity to the P-gp and MRP1 that together with GSH play a protective role.
机译：卡西酮衍生物是新药市场中最具代表性的一类，被认为具有神经毒性。由于卡西酮，如戊烯酮和甲基酮，可作为外消旋体，我们的目标是研究每种对映体诱导的神经元细胞毒性。因此，使用多巴胺能SH-SY5Y细胞系来评估戊烯酮和甲基酮对映体对细胞毒性、氧化应激和膜外排转运的对映选择性假设（通过电子研究证实）。我们的研究证明了这些卡西酮的对映选择性，其中S-（+）-戊烯酮和R-（+）-甲基酮是最具氧化性的对映体，也是最具细胞毒性的，这表明氧化应激是主要的细胞毒性机制，如之前在体外研究中所述。此外，外排转运蛋白多药耐药相关蛋白1（MRP1）似乎与GSH一起，对R-（-）-戊烯酮对映体诱导的细胞毒性发挥选择性保护作用。还观察到与P-糖蛋白（P-gp）结合时具有对映选择性，P-糖蛋白是另一种外排蛋白，R-（-）-戊烯酮和S-（-）-甲基酮是运输最频繁的对映体化合物。这些结果通过电子对接研究得到证实，表明R-（-）-戊烯酮是对MRP1亲和力最高的对映体，S-（-）-甲基酮和R-（-）-戊烯酮是对P-gp亲和力最高的对映体。总之，我们的数据表明，戊烯酮和甲基酮在其细胞毒性中表现出对映选择性，这似乎涉及不同的氧化反应性，以及与GSH一起发挥保护作用的P-gp和MRP1的不同亲和力。

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