Dehydromonocrotaline induces cyclosporine A-insensitive mitochondrial permeability transition/cytochrome c release.
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 microM Ca(2+), DHM (50-250 microM) 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 microM) 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.
dos Santos
Aline Buda
AB
Laboratório de Bioquímica, Faculdade de Zootecnia, Universidade Estadual Paulista Júlio de Mesquita Filho, Campus de Dracena, 17900-000 Dracena, SP, Brazil.
Dorta
Daniel Junqueira
DJ
Pestana
Cezar Rangel
CR
Maioli
Marcos Antonio
MA
Curti
Carlos
C
Mingatto
Fábio Erminio
FE
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D016686:Monocrotaline / Q000031:analogs & derivatives* / Q000494:pharmacology; D009249:NADP / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000477:Alkylating Agents; D007166:Immunosuppressive Agents; D033681:Mitochondrial Membrane Transport Proteins; D013438:Sulfhydryl Compounds; C014114:monocrotaline pyrrole; D009249:NADP; D016686:Monocrotaline; D016572:Cyclosporine; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D005978:Glutathione; D002118:Calcium