PDF(Pubmed)
Abstract：
The most important dose-limiting factor of the anthracycline idarubicin is the high risk of cardiotoxicity, in which the secondary alcohol metabolite idarubicinol plays an important role. It is not yet clear which enzymes are most important for the formation of idarubicinol and which inhibitors might be suitable to suppress this metabolic step and thus would be promising concomitant drugs to reduce idarubicin-associated cardiotoxicity. We, therefore, established and validated a mass spectrometry method for intracellular quantification of idarubicin and idarubicinol and investigated idarubicinol formation in different cell lines and its inhibition by known inhibitors of the aldo-keto reductases AKR1A1, AKR1B1, and AKR1C3 and the carbonyl reductases CBR1/3. The enzyme expression pattern differed among the cell lines with dominant expression of CBR1/3 in HEK293 and MCF-7 and very high expression of AKR1C3 in HepG2 cells. In HEK293 and MCF-7 cells, menadione was the most potent inhibitor (IC50 = 1.6 and 9.8 µM), while in HepG2 cells, ranirestat was most potent (IC50 = 0.4 µM), suggesting that ranirestat is not a selective AKR1B1 inhibitor, but also an AKR1C3 inhibitor. Over-expression of AKR1C3 verified the importance of AKR1C3 for idarubicinol formation and showed that ranirestat is also a potent inhibitor of this enzyme. Taken together, our study underlines the importance of AKR1C3 and CBR1 for the reduction of idarubicin and identifies potent inhibitors of metabolic formation of the cardiotoxic idarubicinol, which should now be tested in vivo to evaluate whether such combinations can increase the cardiac safety of idarubicin therapies while preserving its efficacy.
摘要：
蒽环类抗生素伊达比星最重要的剂量限制因素是心脏毒性的高风险，其中次生醇代谢产物伊达比星醇起重要作用。尚不清楚哪些酶对于伊达比星醇的形成是最重要的,并且哪些抑制剂可能适合于抑制该代谢步骤,因此将是减少伊达比星相关的心脏毒性的有希望的伴随药物。我们,因此,建立并验证了一种用于细胞内定量伊达比星和伊达比星的质谱方法，并研究了不同细胞系中伊达比星的形成及其被已知的醛酮还原酶AKR1A1，AKR1B1和AKR1C3以及羰基还原酶CBR1/3抑制剂的抑制作用。在HEK293和MCF-7中CBR1/3显性表达而在HepG2细胞中AKR1C3非常高表达的细胞系之间，酶的表达模式有所不同。在HEK293和MCF-7细胞中，甲萘醌是最有效的抑制剂（IC50=1.6和9.8µM），而在HepG2细胞中，拉尼司他最有效(IC50=0.4µM)，表明拉尼司他不是一种选择性的AKR1B1抑制剂，但也是AKR1C3抑制剂。AKR1C3的过表达证实了AKR1C3对伊达比星醇形成的重要性，并表明雷尼司他也是该酶的有效抑制剂。一起来看,我们的研究强调了AKR1C3和CBR1对减少伊达比星的重要性，并确定了心脏毒性伊达比星代谢形成的有效抑制剂，现在应该在体内进行测试，以评估此类组合是否可以增加伊达比星疗法的心脏安全性，同时保留其功效。
