Anthracycline derivatives inhibit cardiac CYP2J2.
Anthracycline derivatives inhibit cardiac CYP2J2.
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DOI：
10.1016/j.jinorgbio.2022.111722
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发表时间：
2022-04
影响因子：
3.9
通讯作者：
Das A
中科院分区：
文献类型：
--
作者：
Kim JS;Arango AS;Shah S;Arnold WR;Tajkhorshid E;Das A
蒽环类化疗药物是非常有效的，但它们的临床实用性，如果受到不利的副作用，如心脏毒性。细胞色素P450 2 J2（CYP 2 J2）是人心肌细胞中的细胞色素P450环氧合酶，其将花生四烯酸（AA）转化为心脏保护性的环氧二十碳三烯酸（EET）区域异构体。在此，我们进行了生化研究，以了解蒽环类药物衍生物（柔红霉素、阿霉素、表阿霉素、伊达比星、5-亚氨基柔红霉素、佐柔比星、戊柔比星和阿克拉霉素）与CYP 2 J2的相互作用。我们利用荧光偏振（FP）来评估蒽环类药物是否与CYP 2 J2结合。我们发现，阿克拉维汀与CYP 2 J2的结合最强，尽管它具有庞大的基团。我们确定依巴斯汀竞争性抑制蒽环类药物结合，表明依巴斯汀和蒽环类药物可能具有相同的结合位点。分子动力学和系综对接揭示了蒽环类药物和CYP 2 J2之间的静电相互作用，有助于结合稳定性。特别是，蒽环类药物中的葡糖胺基团通过与CYP 2 J2中的谷氨酸和天冬氨酸残基结合形成盐桥相互作用而稳定。此外，我们使用迭代系综对接计划来衡量蒽环类药物对EET区域异构体的生产和蒽环类药物对AA代谢的抑制的影响。随后采用液相色谱串联质谱裂解分析对CYP 2 J2介导的蒽环类衍生物代谢进行实验验证，并通过这些衍生物抑制CYP 2 J2介导的AA代谢。总之，我们使用实验和理论方法来揭示蒽环类衍生物与CYP 2 J2的相互作用。这些研究将有助于确定蒽环类药物心脏毒性如何通过抑制心脏P450介导的替代机制，这将有助于设计毒性较低的新蒽环类药物衍生物。
Anthracycline chemotherapeutics are highly effective, but their clinical usefulness if hampered by adverse side effects such as cardiotoxicity. Cytochrome P450 2J2 (CYP2J2) is a cytochrome P450 epoxygenase in human cardiomyocytes that converts arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acid (EET) regioisomers. Herein, we performed biochemical studies to understand the interaction of anthracycline derivatives (daunorubicin, doxorubicin, epirubicin, idarubicin, 5-iminodaunorubicin, zorubicin, valrubicin, and aclarubicin) with CYP2J2. We utilized fluorescence polarization (FP) to assess whether anthracyclines bind to CYP2J2. We found that aclarubicin bound the strongest to CYP2J2 despite it having large bulky groups. We determined that ebastine competitively inhibits anthracycline binding, suggesting that ebastine and anthracyclines may share the same binding site. Molecular dynamics and ensemble docking revealed electrostatic interactions between the anthracyclines and CYP2J2, contributing to binding stability. In particular, the glycosamine groups in anthracyclines are stabilized by binding to glutamate and aspartate residues in CYP2J2 forming salt bridge interactions. Furthermore, we used iterative ensemble docking schemes to gauge anthracycline influence on EET regioisomer production and anthracycline inhibition on AA metabolism. This was followed by experimental validation of CYP2J2-mediated metabolism of anthracycline derivatives using liquid chromatography tandem mass spectrometry fragmentation analysis and inhibition of CYP2J2-mediated AA metabolism by these derivatives. Taken together, we use both experimental and theoretical methodologies to unveil the interactions of anthracycline derivatives with CYP2J2. These studies will help identify alternative mechanisms of how anthracycline cardiotoxicity may be mediated through the inhibition of cardiac P450, which will aid in the design of new anthracycline derivatives with lower toxicity.
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影响因子：
105.7
作者：
BONADONNA, G;MONFARDINI, S;FOSSATIB.F
通讯作者：
FOSSATIB.F
DOI：
10.1016/j.ijbiomac.2014.02.028
发表时间：
2014-05-01
影响因子：
8.2
作者：
Agudelo, Daniel;Bourassa, Philippe;Tajmir-Riahi, Heidar-Ali
通讯作者：
Tajmir-Riahi, Heidar-Ali
细胞色素P450的合作特性。
影响因子：
13.5
作者：
Denisov IG;Frank DJ;Sligar SG
通讯作者：
Sligar SG
影响因子：
2.9
作者：
Arnold WR;Baylon JL;Tajkhorshid E;Das A
通讯作者：
Das A
影响因子：
3.8
作者：
ARCAMONE, F;CASSINEL.G;SPALLA, C
通讯作者：
SPALLA, C