Disseleneto de difenila: um organocalcogênio com baixa toxicidade em não roedores e importantes propriedades anti-aterogênicas em modelos in vivo e in vitro

Abstract

Atherosclerosis is a chronic inflammatory condition associated with an overproduction of oxidant species. Since low density lipoprotein (LDL) oxidation plays a key role in the pathogenesis of atherosclerosis, antioxidants that can inhibit this oxidative process might be useful in preventing atherosclerosis-related pathological conditions, such as cardiovascular diseases and stroke. Here, we investigated the potential toxicological effects and the anti-atherogenic properties of diphenyl diselenide (PhSe)2, a simple organoselenium compound that presents important antioxidant properties. Toxicological studies, revealed that (PhSe)2, orally administered, produced minor toxicological effects in rabbits exposure for a long term. The toxic potential of (PhSe)2 was evidenced by a decrease in the ascorbic acid contents in blood, liver and brain of rabbits. Nevertheless, the prolonged exposition with (PhSe)2 was not hepato or renotoxic and not modified the others oxidative stress parameters. The consumption of (PhSe)2 by hipercholesterolemic rabbits significantly decreased the serum cholesterol levels and also diminished the serum and hepatic levels of TBARS, as well as the production of free radical species in blood and brain. In vitro studies demonstrated that (PhSe)2 showed a dosedependent protective effect against Cu2+ and 2,2-azobis-2-amidinopropane (AAPH)-induced oxidation of LDL or parinaric acid (PnA) incorporated into isolated human LDL. Interestingly, (PhSe)2 also protected protein moieties from human isolated LDL against Cu2+-induced oxidation. These effects were related to its thiol-peroxidase activity. In experiments with primary cultures of bovine aortic endothelial cells (BAEC), (PhSe)2 protected endothelial cells from the damage promoted by peroxynitrite exposure, in a more effective way than ebselen. The intracellular levels of glutathione (GSH) were almost completely consumed by peroxynitrite and although the compounds did not restore the normal levels, (PhSe)2 per se increases significantly GSH in a concentration-dependent manner. This effect may be related with the significant increase in cellular glutathione peroxidase (GPx) activity promoted by this compound. Taken together, the results indicated that (PhSe)2 is relatively safe for rabbits even after a prolonged time of ingestion and suggest a new role for diphenyl diselenide as a potential anti-atherogenic agent.