Oxidative/Nitrative Mechanism of Molsidomine Mitotoxicity Assayed by the Cytochrome c Reaction with SIN-1 in Models of Biological Membranes

Autor(es)

de Barros, Marcelo Paes ^[1] ; Araujo-Chaves, Juliana Casares ^[2] ; Brito, Adrianne Marlise Mendes ^[2] ; Nantes-Cardoso, Iseli Lourenco ^[2]

Afiliação do(s) autor(es)

^[1] Cruzeiro do Sul Univ, Inst Phys Act Sci & Sports ICAFE, Interdisciplinary Program Hlth Sci, BR-01506000 Sao Paulo, SP - Brazil

^[2] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210580 Santo Andre, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Chemical Research in Toxicology; v. 33, n. 11, p. 2775-2784, NOV 16 2020.
• Citações Web of Science: 0

Resumo

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 lessrhombic 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 center dot with molecular oxygen that attacks LOOH and leads to the formation of substances that are not reactive with thiobarbituric acid. (AU)

• Processo FAPESP: 15/17688-0 - Nanoestruturas Metálicas Associadas a Porfirinas, Citocromo c e Azul de Metileno: Estudos Fundamentais para Aplicações em Sistema Biológicos e Energia
• Beneficiário: Iseli Lourenço Nantes Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/06032-2 - Estratégias bioquímicas, fisiológicas e transcriptômicas para o estudo da relação entre carotenóides, estresse oxidativo e qualidade de frutas cítricas
• Beneficiário: Marcelo Paes de Barros
• Modalidade de apoio: Bolsas no Exterior - Pesquisa
• Processo FAPESP: 17/02317-2 - Interfaces em materiais: propriedades eletrônicas, magnéticas, estruturais e de transporte
• Beneficiário: Adalberto Fazzio
• Modalidade de apoio: Auxílio à Pesquisa - Temático