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首页> 外文期刊>Archives of Toxicology >Induction and activation of P-glycoprotein by dihydroxylated xanthones protect against the cytotoxicity of the P-glycoprotein substrate paraquat.
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Induction and activation of P-glycoprotein by dihydroxylated xanthones protect against the cytotoxicity of the P-glycoprotein substrate paraquat.

机译：二羟基化的氧杂蒽酮对P-糖蛋白的诱导和激活可以防止P-糖蛋白底物百草枯的细胞毒性。

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摘要

Xanthones are a family of compounds with several known biological activities and therapeutic potential for which information on their interaction with membrane transporters is lacking. Knowing that P-glycoprotein (P-gp) acts as a cellular defense mechanism by effluxing its toxic substrates, the aim of this study was to investigate the potential of five dihydroxylated xanthones as inducers of P-gp expression and/or activity and to evaluate whether they could protect Caco-2 cells against the cytotoxicity induced by the toxic P-gp substrate paraquat (PQ). After 24爃 of incubation, all tested xanthones caused a significant increase in both P-gp expression and activity, as evaluated by flow cytometry using the UIC2 antibody and rhodamine 123, respectively. Additionally, after a short 45-min incubation, all the tested xanthones induced a rapid increase in P-gp activity, indicating direct pump activation without increased P-gp protein expression. The tested compounds also increased P-gp ATPase activity in MDR1-Sf9 membrane vesicles, demonstrating to be P-gp substrates. Moreover, when simultaneously incubated with PQ, all xanthones significantly reduced the cytotoxicity of the herbicide, and these protective effects were completely reversed upon incubation with a specific P-gp inhibitor. In silico studies evaluating the interactions between xanthones and P-gp in the presence of PQ suggested that a co-transport mechanism may be operating. A quantitative structure-activity relationship model was developed and validated, and the maximal partial charge for an oxygen atom was the descriptor predicted as being implicated in P-gp activation by the dihydroxylated xanthones. These results disclose new perspectives in preventing PQ- and other P-gp substrates-induced poisonings.
机译：氧杂蒽酮是具有几种已知生物学活性和治疗潜力的化合物家族，其缺乏有关其与膜转运蛋白相互作用的信息。知道P-糖蛋白（P-gp）通过释放其有毒底物而起细胞防御机制的作用，本研究的目的是研究5种二羟基化的氧杂蒽酮作为P-gp表达和/或活性诱导剂的潜力，并评估它们是否可以保护Caco-2细胞免受毒性P-gp底物百草枯（PQ）诱导的细胞毒性。孵育24分钟后，如分别使用UIC2抗体和若丹明123通过流式细胞术评估的那样，所有测试的氧杂蒽酮均导致P-gp表达和活性显着增加。此外，经过短短的45分钟孵育后，所有测试的氧杂蒽酮均诱导P-gp活性迅速增加，表明直接泵浦激活而P-gp蛋白表达未增加。被测化合物还增加了MDR1-Sf9膜囊泡中的P-gp ATPase活性，证明是P-gp底物。此外，当与PQ同时孵育时，所有的氧杂蒽酮均显着降低了除草剂的细胞毒性，与特定的P-gp抑制剂孵育后，这些保护作用被完全逆转。在计算机研究中，在存在PQ的情况下评估氧杂蒽酮与P-gp之间的相互作用的计算机研究表明，共转运机制可能正在发挥作用。建立并验证了定量的构效关系模型，并预测了氧原子的最大部分电荷与二羟化氧杂蒽酮参与P-gp活化有关。这些结果揭示了预防PQ和其他P-gp底物引起的中毒的新观点。

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