Short-term vitamin A supplementation at therapeutic doses induces a pro-oxidative state in the hepatic environment and facilitates calcium-ion-induced oxidative stress in rat liver mitochondria independently from permeability transition pore formation : detrimental effects of vitamin A supplementation on rat liver redox and bioenergetic states homeostasis.
There is a growing body of evidence showing that vitamin A induces toxic effects in several experimental models and in human beings. In the present work, we have investigated the effects of short-term vitamin A supplementation on the adult rat liver redox status. We have found that vitamin A at therapeutic doses induces a hepatic oxidative insult. Furthermore, we have observed increased antioxidant enzyme activity in the liver of vitamin-A-treated rats. Additionally, some mitochondrial dysfunction was found since superoxide anion production was increased in vitamin-A-treated rat liver submitochondrial particles, which may be the result of impaired mitochondrial electron transfer chain activity, as assessed here. We have also isolated rat liver mitochondria and challenged it with 75 muM CaCl2, a non-oxidant agent that is able to induce mitochondrial oxidative stress indirectly. We have found that mitochondria isolated from vitamin-A-treated rat liver are more sensitive to CaCl2 than control mitochondria regarding the redox status. Importantly, vitamin A seems to alter mitochondrial redox status independently of the participation of the mitochondrial permeability transition pore, which is activated by Ca2+ ions since cyclosporin A did not prevent the oxidative insult elicited by Ca2+ addition. Overall, we show here that mitochondria are a target of vitamin-A-associated toxicity also in vivo.
de Oliveira
Marcos Roberto
MR
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Av. Ramiro Barcelos, 2600, Anexo, Lab. 32, Porto Alegre, CEP: 90035-003, RS, Brazil. mrobioq@yahoo.com.br
Oliveira
Max William Soares
MW
Lorenzi
Rodrigo
R
Fagundes da Rocha
Ricardo
R
Fonseca Moreira
José Cláudio
JC
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004579:Electron Transport; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000083162:Mitochondrial Permeability Transition Pore; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D013367:Submitochondrial Particles / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014801:Vitamin A / Q000008:administration & dosage / Q000009:adverse effects
D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013481:Superoxides; D014801:Vitamin A; D016572:Cyclosporine; D010088:Oxidoreductases; D002118:Calcium