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首页> 美国卫生研究院文献>International Journal of Molecular Sciences >Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism
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Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism

机译：毒性吡咯并立烷生物碱的鉴定及其常见的肝毒性机理

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摘要

Pyrrolizidine Alkaloids (PAs) are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH) metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types) in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1) and glutathione peroxidase 1 (GPX1) targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.
机译：吡咯嗪核生物碱（PAs）目前是最重要的植物性肝毒性成分之一。谷胱甘肽（GSH）代谢是PAs肝毒性机制中最报道的途径。我们推测，对于不同的PA，它们在GSH代谢中的肝毒性应该有共同的机制。考虑到当前实验方法的局限性，采用了计算方法来检验我们的假设。首先，通过反向对接确定了22种PA（来自三种主要PA类型）在GSH代谢中的潜在靶点；其次，发现谷胱甘肽S-转移酶A1（GSTA1）和谷胱甘肽过氧化物酶1（GPX1）靶标模式是毒性PA的特殊特征，具有逐步多元线性回归的特点。此外，通过配体-蛋白质相互作用分析证明了毒性PA与这两个靶标之间相互作用的潜在分子机制。最后，GSTA1和GPX1被证明是GSH代谢的重要节点。总体而言，可以通过GSTA1和GPX1靶标模式识别出有毒的PA，这表明它们具有常见的肝毒性机制：干扰GSH代谢中的解毒作用。此外，这里开发的所有策略都可以扩展到其他毒素毒性机理的研究。

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