suggested that retinol supplementation could exert preventive/protective effects against malignant neurodegenerative and cardiovascular diseases since reactive species and oxidative stress play a major role in the pathogenesis and progression of such conditions (Bjelakovic et al 2008; Lee et al 2009; Mongan and Gudas 2007) Nonetheless later clinical and experimental data provided evidence for a pro-oxidant action of retinol and other DNA-PK Inhibitors retinoids at specific conditions Retinol supplementation increased the incidence of lung cancer and cardiovascular diseases in smokers and asbestos-exposed workers (Omenn et al 1994) and enhanced oxidative damage in animal models (Pasquali et al 2009ab 2010).

Retinol and derivatives were also observed to increase reactive species production and oxidative stress in cell cultures (Gelain and Moreira 2008; Gimeno et al 2004) and to enhance free radical production and oxidative damage to DNA in vitro (Murata and Alisertib Kawanishi 2000) We have previously observed that retinol at specific concentrations is able to enhance reactive species production and induce extensive oxidative damage in cultured Sertoli cells (Dal-Pizzol et al 2001a; Pasquali et al 2008) Sertoli cells constitute an excellent model to study different functions of retinol at cellular level as they are physiological targets of vitamin A and diverse endocrine functions are constitutively regulated by retinol and RA in these cells (Hogarth and Griswold 2010; Sanborn et al 1987) Cytosolic concentrations of retinol in physiologic conditions range from 02 to 4C5 M in different cells (Ross 1993; Ross et al 2001; Vicente et al 1998) .

Here and in previous works we observed that retinol enhances free radical production and causes oxidative stress at 7 M while concentrations above this threshold induce extensive cell damage and generalized cell function impairment which causes early cell death by secondary intention necrosis (Klamt et al 2003ab) These results altogether with results from other studies by different authors strongly indicate a potential pro-oxidant capacity of retinol at concentrations slightly above the reported physiological limit to cells In hepatic stellate cells the main site of retinol storage in liver physiologic concentrations of retinol have been reported to range between 2 and 5 M (Ross et al 2001) and liver retinol content was observed to increase from 3 up to 20-fold (levels considered toxic) in adults taking highly enriched supplementations (Allen and Haskell 2002) .