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Oxidative/Nitrative Mechanism of Molsidomine Mitotoxicity Assayed by the Cytochrome c Reaction with SIN-1 in Models of Biological Membranes.
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2020-07-24 , DOI: 10.1021/acs.chemrestox.0c00122
Marcelo Paes de Barros 1 , Juliana Casares Araujo-Chaves 2 , Adrianne Marlise Mendes Brito 2 , Iseli Lourenço Nantes-Cardoso 2
Affiliation  

Molsidomine is currently used as a vasodilator drug for the treatment of myocardial ischemic syndrome and congestive heart failure, although still presenting some mitochondrial-targeted side effects in many human cells. As a model of molsidomine mitotoxicity, the reaction of cytochrome c with phosphatidylserine (PS)- and cardiolipin (CL)-containing liposomes was investigated in oxidative/nitrosative conditions imposed by SIN-1 decomposition, which renders peroxynitrite (ONOO) as a main reactive product. In these conditions, the production of thiobarbituric acid-reactive substance (TBARs) and LOOH was affected by the lipid composition and the oxidative/nitrative conditions used. The oxidative/nitrative conditions were the exposure of lipids to SIN-1 decomposition, native cytochrome c after previous exposure to SIN-1, concomitantly to SIN-1 and native cytochrome c, native cytochrome c, and cytochrome c modified by SIN-1 that presents a less-rhombic heme iron (L-R cytc). TBARs and LOOH production by lipids and cytochrome c exposed concomitantly to SIN-1 differed from that obtained using L-R cytc and featured similar effects of SIN-1 alone. This result suggests that lipids rather than cytochrome c are the main targets for oxidation and nitration during SIN-1 decomposition. PS- and CL-containing liposomes challenged by SIN-1 were analyzed by Fourier transform infrared spectroscopy that revealed oxidation, trans-isomerization, and nitration. These products are consistent with reaction routes involving lipids and NOx formed via peroxynitrite or direct reaction of NO with molecular oxygen that attacks LOOH and leads to the formation of substances that are not reactive with thiobarbituric acid.

中文翻译:

生物膜模型中通过细胞色素 c 与 SIN-1 反应测定的吗西多明线粒体毒性的氧化/硝化机制。

吗西多明目前被用作血管扩张药,用于治疗心肌缺血综合征和充血性心力衰竭,尽管在许多人体细胞中仍存在一些针对线粒体的副作用。作为 molsidomine 有丝分裂毒性的模型,在 SIN-1 分解施加的氧化/亚硝化条件下研究了细胞色素 c 与含有磷脂酰丝氨酸 (PS) 和心磷脂 (CL) 的脂质体的反应,这使得过氧亚硝酸盐 (ONOO ) 作为主要的反应产物。在这些条件下,硫代巴比妥酸反应性物质 (TBAR) 和 LOOH 的产生受脂质成分和所使用的氧化/硝化条件的影响。氧化/硝化条件是脂质在先前暴露于 SIN-1 后暴露于 SIN-1 分解、天然细胞色素 c、同时暴露于 SIN-1 和天然细胞色素 c、天然细胞色素 c 和由 SIN-1 修饰的细胞色素 c呈现较少菱形的血红素铁 (LR cytc)。伴随着 SIN-1 暴露的脂质和细胞色素 c 产生的 TBARs 和 LOOH 与使用 LR cytc 获得的不同,并且具有与单独 SIN-1 相似的效果。该结果表明脂质而不是细胞色素 c 是 SIN-1 分解过程中氧化和硝化的主要目标。通过傅立叶变换红外光谱分析了由 SIN-1 挑战的含 PS 和 CL 的脂质体,该光谱揭示了氧化、反式异构化和硝化作用。这些产物与脂质和通过过亚硝酸盐形成的 NOx 或 NO 的直接反应形成的反应路线一致分子氧会攻击 LOOH 并导致形成不与硫代巴比妥酸反应的物质。
更新日期:2020-07-24
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