Department of Pharmacodynamics, Medical University of Łódź, Muszynskiego 1, 90-151, Łódź, Poland.
Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska 141/143, 90-236, Łódź, Poland.
Neurotox Res. 2018 Oct;34(3):613-626. doi: 10.1007/s12640-018-9923-1. Epub 2018 Jun 27.
Pyrovalerone derivatives (α-pyrrolidinophenones) form a branch of synthetic cathinones, a second most prominent group of novel psychoactive substances. Although the toxicity of 3,4-MDPV, a progenitor of the α-pyrrolidinophenones, is well described, little is known of the potential cytotoxicity of the new members of this group entering the recreational drug market each year. The present study assesses the cytotoxicity of members of the α-pyrrolidinophenone group, i.e., α-PVP, its longer side-chain derivatives PV8 and PV9, and their 4-fluoro- and 4-methoxy-analogs, against model cell lines for the nervous system (SH-SY5Y), liver (Hep G2) and upper airway epithelium (RPMI 2650), and cardiomyocytes (H9C2(2-1)). Additionally, an impact of pyrovalerones on the fluidity of the plasma membrane, as the potential mechanism of their cytotoxicity, was examined. The longer side-chain α-pyrrolidinophenones and their fluoro- and methoxy-analogs produce more pronounced maximal cytotoxicity, with regard to mitochondrial activity and cell membrane integrity, than the five-carbon α-PVP and its substituted derivatives. The report demonstrates, for the first time, that changes of fluidity of the interior part of plasma membrane contribute to the cytotoxicity of pyrovalerone derivatives, in addition to the previously reported mechanisms. Taking into consideration our previous findings that PV8 and PV9 produce weaker psychostimulatory effects than α-PVP, the higher cytotoxicity of the new generation of pyrovalerones can pose a serious threat to abusers, as it is possible that longer-chain compounds may be taken in higher doses to obtain similar levels of stimulation.
吡咯烷酮衍生物（α-吡咯烷苯酮）属于合成卡西酮的一个分支，是新型精神活性物质的第二大主要类别。虽然 3,4-MDPV（α-吡咯烷苯酮的前体）的毒性已有详细描述，但对于每年进入娱乐性药物市场的该类别的新成员的潜在细胞毒性知之甚少。本研究评估了 α-吡咯烷苯酮类别的成员，即 α-PVP、其长侧链衍生物 PV8 和 PV9 及其 4-氟代和 4-甲氧基类似物，对神经系统模型细胞系（SH-SY5Y）、肝脏（Hep G2）和上呼吸道上皮（RPMI 2650）以及心肌细胞（H9C2(2-1)）的细胞毒性。此外，还研究了吡咯烷酮对质膜流动性的影响，这可能是其细胞毒性的潜在机制。长侧链的 α-吡咯烷苯酮及其氟代和甲氧基类似物比五碳 α-PVP 及其取代衍生物对线粒体活性和细胞膜完整性产生更明显的最大细胞毒性。该报告首次表明，除了先前报道的机制外，质膜内部流动性的变化也有助于吡咯烷酮衍生物的细胞毒性。考虑到我们之前的发现，即 PV8 和 PV9 产生的精神刺激作用比 α-PVP 弱，新一代吡咯烷酮衍生物的更高细胞毒性可能对使用者构成严重威胁，因为长链化合物可能会被摄入更高剂量以获得类似水平的刺激。
