Efeito da administração crônica de metionina e/ou metionina sulfóxido sobre o status redox, sistema purinérgico e fenótipo de macrófagos peritoneais de camundongos

Abstract

Hypermetioninemia is a disease characterized by the deficiency or absence of the enzyme methionine adenosyltransferase (MAT), this condition results in high blood levels of methionine (Met) and its metabolites, such as methionine sulfoxide (MetO). Hypermethioninemic patients may present with neurological and hepatic disorders involving inflammation and oxidative stress, but the pathophysiology of these events remains unclear. Thus, the objective of the present study was to investigate the effect of chronic administration of Met and/or MetO on the phenotype expressed by peritoneal macrophages of young mice, evaluating inflammatory, oxidative stress and purinergic parameters. The animals were divided into four groups: I (control); II (Met); III (MetO) and IV (Met + MetO). In this protocol, the animals received a subcutaneous injection of Met (0.35 - 1.2 g/kg) and/or MetO (0.09-0.3 g/kg) from 10 to 38 days of life, twice daily, with an 8-hour interval between applications. The results demonstrated that Met and/or MetO induced a M1/classical activation phenotype in peritoneal macrophages, observed through increased levels of tumor necrosis factor α (TNF-α) and nitrite, and reduction of arginase activity. In addition, Met and/or MetO also altered the activity of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, as well as total thiol content and levels of reactive oxygen species in the peritoneal macrophages. Finally, chronic administration of Met and/or MetO promoted alteration in the hydrolysis of adenine nucleotides ATP and ADP, observed through the increase in ectonucleotidase activity. These findings demonstrated a M1/classical macrophage polarization, alterations in the redox status and purinergic system, which may contribute to the understanding of alterations present in hypermethioninemic patients, in order to aid in the search for new therapeutic targets.