Molecular Mechanisms of microcystin-LR cytotoxicity in sub-chronic intoxicated mice.

N. LEZCANO; I. LUCOTTI; D. SEDAN; A. MATTIAZZI; D. ANDRINOLO; C MUNDIÑA-WEILENMAN

Estambul

Congreso; The 8th International Conference on Toxic Cyanobacteria (ICTC8); 2010

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman";} @page Section1 {size:595.3pt 841.9pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:35.4pt; mso-footer-margin:35.4pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> 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 ans 2 A (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 decrease of PP1 and PP2A activity, decrease alpha tubulina expression and increase phosphorylation of p38-MAPKand CaMKII. Sub-chronic MC-LR intoxication induce 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.