CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Molecular mechanisms of microcystin-LR cytotoxicity in sub-chronic intoxicated mice.
LEZCANO N; LUCOTTI I; ANDRINOLO D; SEDÁN D; MATTIAZZI A; MUNDIÑA - WEILENMANN C
Congreso; 8th International Conference on Toxic Cyanobacterias; 2010
Microcystin-LR (MC-LR) is a hepatotoxin produced by several bloom-forming cyanobacteria of fresh water. Acute lethal cytotoxicity and tumor promoting activity of MC-LR is attributed to its ability to inhibit serine/threonine phosphatases type 1 and 2 (PP1, PP2A) which leads to excessive protein phosphorylation, alterations in cytoskeleton and subsequent cell destruction. Chronic exposure to low concentrations of MC-LR through consumption of contaminated water is most likely to occur and its consequences are less well studied. We investigated the mechanisms of MC-LR cytotoxicity in mice treated i.p. with 25 micrograms MC-LR/kg body weight or saline solution every 2 days for a month. Apoptosis, determined by DNA-laddering and the ratio between pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) proteins, increased only in liver from treated animals. Analysis of liver extracts demonstrated a decreased PP1 and PP2A activity, decreased alpha-tubulin expression and increased phosphorylation of p38-MAPK and CaMKII. Sub-chronic MC-LR intoxication induces apoptosis and cytoskeletal disruption in hepatocytes, presumably mediated by the inhibition of phosphatases which causes CaMKII and p38 MAPK activation and phosphorylation events leading to cell death.