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首页> 外文期刊>Toxicology Letters: An International Journal Providing a Forum for Original and Pertinent Contributions in Toxicology Research >Tools for studying the metabolism of new psychoactive substances for toxicological screening purposes - A comparative study using pooled human liver S9, HepaRG cells, and zebrafish larvae
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Tools for studying the metabolism of new psychoactive substances for toxicological screening purposes - A comparative study using pooled human liver S9, HepaRG cells, and zebrafish larvae

机译：用于研究毒理学筛查新精神活性物质新陈代谢的工具 - 一种使用合并的人肝S9，Heparg细胞和斑马鱼幼虫的对比研究

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New psychoactive substances (NPS) are an emerging topic amongst abused compounds. New varieties appear constantly on the market, without any knowledge about their toxicodynamic and/or -kinetic properties and knowledge of their metabolism is crucial for the development of analytical methods employed for their detection. Controlled human studies would of course be best suited but due to ethical reasons and lack of preclinical safety data, they are usually not available. Often, in vitro models are used to evaluate similarities to human in vivo hepatic phase I and II metabolism and systems explored include primary human hepatocytes, pooled human S9 fraction, and HepaRG, a human hepatic cell line. All these in vitro models have considerable limitations and drug distribution, reabsorption, enterohepatic circulation, and renal elimination cannot be studied. In the recent years, zebrafish (Danio rerio) larvae (embryos) were discussed as a potential in vivo model to overcome these limitations. To date, no studies demonstrating its suitability for studying NPS metabolism in the context of analytical toxicology are available. The aim of this study was to elucidate whether zebrafish larvae can serve as a surrogate for human hepatic metabolism of NPS to develop toxicological screening procedures. Here, we used methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo[ 2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7'N-5F-ADB), a new synthetic cannabinoid, whose human metabolism was recently described in the literature, as a model compound to evaluate zebrafish larvae as a new tool for metabolism studies. Different conditions for zebrafish larvae and HepaRG protocols were tested. As zebrafish larvae and HepaRG cell incubations provided the highest number of metabolites and the most authentic spectrum of human metabolites. The most suitable larvae protocol was the incubation via medium and the analysis of the extracted zebrafish larvae. The zebrafish larvae model might be a promising preclinical surrogate for human hepatic metabolism of NPS.
机译：新的精神活性物质（NPS）是滥用化合物中的新兴主题。新品种在市场上不断出现，没有任何关于他们的毒动力学和/或 - 基因特性的知识和他们的新陈代谢知识对于他们检测的分析方法的发展至关重要。受控人类研究当然是最适合但由于道德原因和缺乏临床前安全数据，它们通常不可用。通常，在体外模型用于评估对人类的体内肝相I和II代谢和系统的相似性，包括原发性人肝细胞，合并人S9分数和肝癌，人类肝细胞系。所有这些体外模型都具有相当的局限性和药物分布，重吸收，肠内循环和肾脏消除不能研究。近年来，Zebrafish（Danio Rerio）幼虫（胚胎）被讨论为体内模型的潜力来克服这些限制。迄今为止，没有研究在分析毒理学的背景下，可以证明其在研究NPS代谢的适用性。本研究的目的是阐明斑马鱼幼虫是否可以作为NPS的人类肝脏代谢的替代品，以发展毒理学筛查程序。在这里，我们使用甲基2-（1-（5-氟戊基）-1H-吡咯烷[2,3-B]吡啶-3-羧酰胺）-3,3-二甲基丁醛（7'N-5F-ADB），一种新的人类代谢最近在文献中描述的合成大麻素，作为模型化合物，以评估斑马鱼幼虫作为新陈代谢研究的新工具。测试了斑马鱼幼虫和肝病方案的不同条件。作为斑马鱼幼虫和肝细胞孵育提供了最多的代谢物数量和最真实的人代谢物。最合适的幼虫方案是通过培养基孵育和提取的斑马鱼幼虫的分析。斑马鱼幼虫模型可能是NPS人类肝脏代谢的有希望的临床前替代。

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