Cyanotoxins, among which >200 variants of Microcystins (MC), constitute an emerging issue in food safety. Microcystins (MC) toxicity is congener-specific; however, the in vitro inhibition of PP1/PP2A (the key molecular event of MC toxicity) by single MC variants is comparable and MC toxicokinetics seems to be the critical point. Here, the variability in GSH conjugation catalysed by human recombinant enzymes and human hepatic cytosol has been compared between hydrophilic (MC-LR and MC-RR) and hydrophobic (MC-LW, MC-YR and MC-LF) variants, according to measured logPow. In vitro detoxication reaction (spontaneous plus enzymatic) is favored by the variant hydrophilicity, with MC-LF very poorly detoxified. With MC-YR and -LW the spontaneous reaction always gave the major contribution, whereas with MC-LR and -RR the enzymatic reaction became by far predominant when GSH was depleted. Consequently, the well-known GST polymorphisms seems not to be the major driver for potential human variability in susceptibility towards the MC-toxicity, except for MC-RR and -LR when GSH is depleted. Looking at these results and literature data, MC-RR (the least cytotoxic and acutely toxic in rodents) is the more hydrophilic, has the lowest OATP-mediated hepatic uptake and the highest detoxication efficiency. The opposite is true for the most lipophilic MC-LF: once entered in the cells with the highest uptake, it is very poorly detoxified, and resulted as the most toxic in various cell types. MC-dependent TK should be considered in order to estimate the variability in toxicity and to support the use of quantitative in vitro-in vivo extrapolation models of single toxins and their mixtures co-occurring in the environment.

中文翻译：

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人体样本中微囊藻毒素的体外解毒：具有不同亲水性和结构的变异体之间的差异

蓝藻毒素，其中超过 200 种微囊藻毒素 (MC) 变体，构成了食品安全中的一个新问题。微囊藻毒素 (MC) 毒性是同源物特异性的；然而，单个 MC 变体对 PP1/PP2A（MC 毒性的关键分子事件）的体外抑制具有可比性，并且 MC 毒代动力学似乎是关键点。在这里，根据测量的结果，比较了亲水（MC-LR 和 MC-RR）和疏水（MC-LW、MC-YR 和 MC-LF）变体之间由人重组酶和人肝细胞溶质催化的 GSH 结合的变异性。登录 变体亲水性有利于体外解毒反应（自发加酶），而 MC-LF 解毒效果很差。对于 MC-YR 和 -LW，自发反应总是做出主要贡献，而对于 MC-LR 和 -RR，当 GSH 耗尽时，酶促反应变得占主导地位。因此，众所周知的 GST 多态性似乎不是人类对 MC 毒性易感性的潜在变异的主要驱动因素，除了当 GSH 耗尽时 MC-RR 和 -LR。从这些结果和文献数据来看，MC-RR（对啮齿动物的细胞毒性和急性毒性最低）亲水性更强，具有最低的 OATP 介导的肝脏摄取和最高的解毒效率。最亲脂性的 MC-LF 恰恰相反：一旦进入吸收率最高的细胞，它的解毒能力非常差，并且在各种细胞类型中毒性最强。