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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

Abstract

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 μM 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.

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Abbreviations

CsA:

Cyclosporin A

METC:

Mitochondrial electron transfer chain

MPTP:

Mitochondrial permeability transition pore

SMP:

Submitochondrial particles

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Acknowledgments

This work was supported by grants of CNPq, FAPERGS, and PROPESQ-UFRGS. M.R. de Oliveira, M.W.S. Oliveira, R. Lorenzi, and R.F. da Rocha are recipients of CNPq fellowships.

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Correspondence to Marcos Roberto de Oliveira.

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de Oliveira, M.R., Oliveira, M.W.S., Lorenzi, R. et al. 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. Cell Biol Toxicol 25, 545–560 (2009). https://doi.org/10.1007/s10565-008-9111-9

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Keywords

  • Vitamin A
  • Oxidative stress
  • Rat liver
  • Mitochondria
  • Calcium ions