Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Gabriela Narutowicza Str. 11/12, 80-233 Gdańsk, Poland.
Molecules. 2022 Aug 17;27(16):5252. doi: 10.3390/molecules27165252.
The effectiveness of many anticancer drugs depends on the creation of specific metabolites that may alter their therapeutic or toxic properties. One significant route of biotransformation is a conjugation of electrophilic compounds with reduced glutathione, which can be non-enzymatic and/or catalyzed by glutathione-dependent enzymes. Glutathione usually combines with anticancer drugs and/or their metabolites to form more polar and water-soluble glutathione S-conjugates, readily excreted outside the body. In this regard, glutathione plays a role in detoxification, decreasing the likelihood that a xenobiotic will react with cellular targets. However, some drugs once transformed into thioethers are more active or toxic than the parent compound. Thus, glutathione conjugation may also lead to pharmacological or toxicological effects through bioactivation reactions. My purpose here is to provide a broad overview of the mechanisms of glutathione-mediated conjugation of anticancer drugs. Additionally, I discuss the biological importance of glutathione conjugation to anticancer drug detoxification and bioactivation pathways. I also consider the potential role of glutathione in the metabolism of unsymmetrical bisacridines, a novel prosperous class of anticancer compounds developed in our laboratory. The knowledge on glutathione-mediated conjugation of anticancer drugs presented in this review may be noteworthy for improving cancer therapy and preventing drug resistance in cancers.
许多抗癌药物的疗效取决于特定代谢物的产生，这些代谢物可能改变其治疗或毒性特性。一种重要的生物转化途径是将亲电化合物与还原型谷胱甘肽结合，这可以是非酶促的，也可以由谷胱甘肽依赖的酶催化。谷胱甘肽通常与抗癌药物及其代谢物结合，形成更具极性和水溶性的谷胱甘肽 S-缀合物，易于排出体外。在这方面，谷胱甘肽在解毒中发挥作用，降低了外来物质与细胞靶标反应的可能性。然而，一些一旦转化为硫醚的药物比母体化合物更具活性或毒性。因此，通过生物活化反应，谷胱甘肽缀合也可能导致药理学或毒理学效应。我在这里的目的是提供一个广泛的概述，介绍谷胱甘肽介导的抗癌药物缀合的机制。此外，我还讨论了谷胱甘肽缀合对抗癌药物解毒和生物活化途径的生物学重要性。我还考虑了谷胱甘肽在我们实验室开发的新型抗癌化合物非对称双吖啶类药物代谢中的潜在作用。本综述中介绍的关于抗癌药物谷胱甘肽介导缀合的知识，对于改善癌症治疗和预防癌症耐药性可能具有重要意义。
