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

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 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.

Vitamin A supplementation for different periods alters rat vascular redox parameters

“…For SOD activity, our results are not in agreement to other works, since we observed decreased activity after 3 and 28 days treatment period (no modifications after 7 days) while there was a reported increased SOD activity in liver (acutely and chronically) and hypothalamus (chronic period) [10][11][12]. However, one more time we have to consider the organ analyzed and the fact that a very few studies have done oxidative stress parameters analysis in vascular level.…”

“…Interestingly, SH is increased just after 3 days treatment period, the unique period that TBARS had no changes, and did not play modifications after 7 or 28 days treatment period, the same one in which TBARS is diminished [25]. The results presented here, in part, are in accordance to previous works, which found no modifications on SH content after 7 or 28 days treatment period, with identical doses to those tested here, but a difference is notated after 3 days, since in the present study was observed an increase while in the prior a decrease was found [11,12]. Despite the opposite results after 3 days, a coincidence is played, it is exactly in this period that occur the changes, independently if it is to up or down.…”

“…Our results about CAT activity are in accordance with our previous works, which an increase on hepatic activity after 3 days treatment period, and no changes after 28 days treatment period were demonstrated; no modifications of hypothalamus CAT activity after 28 days treatment period were also observed as well. The only exception is the CAT activity after 7 days treatment period, which did not change in the liver in the previous work, but increased in aorta in the present work [10][11][12]. In response to retinol deficiency, CAT activity has played a diminished activity [16].…”

“…On lipoperoxidation terms, we could observe a decrease on TBARS levels in response to the retinyl palmitate treatment, acutely (7 days) and chronically, what is not in agreement to previous results of our group for other tissues. In the liver of animals treated with retinyl palmitate, it was detected an increase on TBARS levels in one treated for acute (3 days) and chronic period [11,12]. When evaluated in the hypothalamus, TBARS levels are also increased in a chronic treatment period [10].…”

Influence of a 50 Hz magnetic field and of all-trans‑retinol on the proliferation of human cancer cell lines

“…In fact, recent studies have provided evidence that retinol could enhance carcinogenesis, especially at doses that exceed the normal dietary intake or in conditions of enhanced oxidative stress (40)(41)(42)(43). This evidence would be supported by the results of a number of experimental studies in different biological systems, in vivo and in vitro, showing that pro-vitamin A, β-carotene, retinol and retinoids have pro-oxidant properties, which might lead to cell oxidative damage and carcinogenesis (44)(45)(46)(47)(48). Thus, in the present scenario of apparently contradictory evidence, further research is needed in order to elucidate the mechanism(s) by which retinoids may influence human carcinogenesis.…”