Oxidative/Nitrative Mechanism of Molsidomine Mitotoxicity Assayed by the Cytochrome c Reaction with SIN-1 in Models of Biological Membranes
| Autor: | Juliana C. Araujo-Chaves, Adrianne M. M. Brito, Marcelo Paes de Barros, Iseli L. Nantes-Cardoso |
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| Rok vydání: | 2020 |
| Předmět: |
Molsidomine
Cytochrome Thiobarbituric acid Oxidative phosphorylation 010501 environmental sciences Toxicology Models Biological 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Cardiolipin TBARS Humans 030304 developmental biology 0105 earth and related environmental sciences 0303 health sciences Molecular Structure biology Cytochrome c Cytochromes c General Medicine Biochemistry chemistry Mitochondrial Membranes biology.protein Oxidation-Reduction Peroxynitrite |
| Zdroj: | Chemical Research in Toxicology. 33:2775-2784 |
| ISSN: | 1520-5010 0893-228X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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