Oxidative/Nitrative Mechanism of Molsidomine Mitotoxicity Assayed by the Cytochrome c Reaction with SIN-1 in Models of Biological Membranes.
Chem Res Toxicol
; 33(11): 2775-2784, 2020 11 16.
Article
em En
| MEDLINE
| ID: mdl-32706246
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Molsidomina
/
Citocromos c
/
Membranas Mitocondriais
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Modelos Biológicos
Limite:
Humans
Idioma:
En
Revista:
Chem Res Toxicol
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Estados Unidos