Retinol, at concentrations greater than the physiological limit, induces oxidative stress and apoptosis in human dermal fibroblasts

Abstract

We have investigated the dose (in the range of microM) and time-dependent effects of four different retinoids (retinol, retinal, retinoic acid and retinol palmitate) on human dermal fibroblasts cultivated in vitro. Retinol and retinal, at a concentration of 20 microM, caused cell damage as evaluated by lactate dehydrogenase activity released into the culture medium. The oxidised glutathione (GSSG)/reduced glutathione (GSH) ratio and malondialdehyde production indicated that 20 microM of retinol provoked oxidative stress in the cultivated human fibroblasts. In the first 8 h after retinol treatment the levels of p53 and Bax proteins as well as caspase 3 activity increased, suggesting apoptotic cell death during the first hours of treatment. If the retinol treatment exceeded 18-24 h we observed necrotic cell death. Vitamin E and coenzyme Q(10) had a protective effect against oxidative stress generated by retinol. Both antioxidant molecules reduced retinol uptake, and in the case of vitamin E the expression of CRABP-II mRNA was induced, providing a plausible explanation for its protective effect.

Differential effects of retinol and retinoic acid on cell proliferation: A role for reactive species and redox-dependent mechanisms in retinol supplementation

“…Previous works reported that ROH and retinaldehyde, but not RA, induce redox-dependent cell death in human fibroblasts [10]. In PC12 cells was observed an increased RS formation following ROH treatment, which was not detected in RA treated-cells [9].…”

“…Studies have suggested that ROH and its principal metabolite RA present different redox-active properties in biological systems [9,10]. Previous works reported that ROH and retinaldehyde, but not RA, induce redox-dependent cell death in human fibroblasts [10].…”

Vitamin A deficiency alters rat lung alveolar basement membrane Reversibility by retinoic acid☆

“…The MDA increment induced by retinoic acid seems to be a surprising result in the light of the antioxidant function shown for retinoids [47]. However, many studies in cultured cells have already described the pro-oxidant action of retinoic acid and other vitamin A derivatives [48][49][50]. In this sense and in agreement with our result, it has been published recently that retinoic acid induces a pro-oxidant condition in cultured Sertoli cells, leading to increased lipid peroxidation, DNA oxidative damage and cell death [50,51].…”

Asiaticoside induces cell proliferation and collagen synthesis in human dermal fibroblasts

“…Gimemo et al (15) investigated the timedependency effect of four different retinoids in the µM dose range on human dermal fibroblasts cultivated in vitro. This study showed that retinol and retinal at concentrations greater than 20 µM, can damage cells as evaluated by lactate dehydrogenase activity released into the culture medium, and induce oxidative stress and apoptosis in human dermal fibroblasts.…”