Carbon monoxide releasing molecule 401 (CORM-401) modulates phase I metabolism of xenobiotics.
Carbon monoxide releasing molecule 401 (CORM-401) modulates phase I metabolism of xenobiotics.
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DOI：
10.1016/j.tiv.2019.04.018
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发表时间：
2019-09
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影响因子：
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通讯作者：
Moritz Walter;W. Stahl;P. Brenneisen;A. Reichert;David Stucki
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作者：
Moritz Walter;W. Stahl;P. Brenneisen;A. Reichert;David Stucki
除了其已被充分研究的毒性之外，一氧化碳（CO）还被认为是各种细胞过程中的信号分子。因此，CO释放分子（CORM）的基础研究和药物开发的相当大的兴趣。本研究的目的是调查，如果CO，从CORM释放，抑制细胞色素P450依赖的单加氧酶（CYP）的活性和调节异生物质代谢。CORM-401用作模型CO递送化合物;不能释放CO的无活性CORM-401（iCORM-401）用作对照化合物。使用无细胞肌红蛋白测定法验证C 0 RM-401而非iC 0 RM-401的CO释放。用重组的RESPONSE和HepG 2细胞通过7-乙氧基试卤灵-O-脱乙基化（EROD）显示了CO依赖性的RESPONSE活性抑制。在CORM-401暴露后，重组EROD活性呈浓度依赖性降低，而iCORM-401没有影响。在高于50 μM CORM-401的浓度下，用CORM-401处理降低HepG 2细胞中的EROD活性，而iCORM-401显示无作用。在给定浓度下，细胞活力不受影响。选择阿米替林作为模型异生素，用高效液相色谱法测定了其代谢产物去甲替林在重组大肠杆菌中的形成。CORM-401处理抑制去甲替林的形成，而iCORM-401处理不抑制。总体而言，我们证明了CO介导的抑制作用时，应用CORM的活性。由于CORM目前正在药物开发中，研究结果强调了考虑这类化合物可能干扰异生物质代谢的重要性。
Next to its well-studied toxicity, carbon monoxide (CO) is recognized as a signalling molecule in various cellular processes. Thus, CO-releasing molecules (CORMs) are of considerable interest for basic research and drug development. Aim of the present study was to investigate if CO, released from CORMs, inhibits cytochrome P450-dependent monooxygenase (CYP) activity and modulates xenobiotic metabolism. CORM-401 was used as a model CO delivering compound; inactive CORM-401 (iCORM-401), unable to release CO, served as control compound. CO release from CORM-401, but not from iCORM-401, was validated using the cell free myoglobin assay. CO-dependent inhibition of CYP activity was shown by 7-ethoxyresorufin-O-deethylation (EROD) with recombinant CYP and HepG2 cells. Upon CORM-401 exposure EROD activity of recombinant CYP decreased concentration dependently, while iCORM-401 had no effect. Treatment with CORM-401 decreased EROD activity in HepG2 cells at concentrations higher than 50 μM CORM-401, while iCORM-401 showed no effect. At the given concentrations cell viability was not affected. Amitriptyline was selected as a model xenobiotic and formation of its metabolite nortriptyline by recombinant CYP was determined by HPLC. CORM-401 treatment inhibited the formation of nortriptyline whereas iCORM-401 treatment did not. Overall, we demonstrate CO-mediated inhibitory effects on CYP activity when applying CORMs. Since CORMs are currently under drug development, the findings emphasize the importance to take into account that this class of compounds may interfere with xenobiotic metabolism.