Dehydromonocrotaline induces cyclosporine A-insensitive mitochondrial permeability transition/cytochrome c release

Autor(es)

dos Santos, Aline Buda ^[1] ; Dorta, Daniel Junqueira ^[2] ; Pestana, Cezar Rangel ^[3] ; Maioli, Marcos Antonio ^[1] ; Curti, Carlos ^[3] ; Mingatto, Fabio Erminio ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Paulista, Lab Bioquim, Fac Zootecnia, BR-17900000 Dracena, SP - Brazil

^[2] Univ Sao Paulo, Dept Quim, Fac Filosofia Ciencias & Letras Ribeirao Preto, BR-14040901 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Dept Quim & Fis, Fac Ciencias Farmaceut, BR-14040903 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Toxicon; v. 54, n. 1, p. 16-22, JUL 2009.
• Citações Web of Science: 11

Resumo

Monocrotaline (MCT) is a pyrrolizidine alkaloid present in plants of the genus Crotalaria that causes cytotoxicity and genotoxicity in animals and humans. It is well established that the toxicity of MCT results from its hepatic bioactivation to dehydromonocrotaline (DHM), an alkylating agent, but the exact mechanism of action remains unknown. In a previous study, we demonstrated DHM's inhibition of mitochondrial NADH-dehydrogenase activity at micromolar concentrations, which is an effect associated with a significant reduction in ATP synthesis. As a follow-up study, we have evaluated the ability of DHM to induce mitochondrial permeability transition (MPT) and its associated processes in isolated rat liver mitochondria. In the presence of 10 mu M Ca(2+), DHM (50-250 mu M) elicited MPT in a concentration-dependent, but cyclosporine A-independent manner, as assessed by mitochondrial swelling, which is associated with mitochondrial Ca(2+) efflux and cytochrome c release. DHM (50-250 mu M) did not cause hydrogen peroxide accumulation but did deplete endogenous glutathione and NAD(P)H, while oxidizing protein thiol groups. These results potentially indicate the involvement of mitochondria, via apoptosis, in the well-documented cytotoxicity of monocrotaline. (C) 2009 Elsevier Ltd. All rights reserved. (AU)

• Processo FAPESP: 04/09882-7 - Efeitos do alcalóide pirrolizidínico monocrotalina em mitocôndrias e hepatócitos isolados de rato
• Beneficiário: Fábio Erminio Mingatto
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores