New Insights on the Mode of Action of Microcystins in Animal Cells - A Review.

Microcystins (MCs) are the most commonly occurring hepatotoxins produced by cyanobacteria. The inhibition of PP2A is widely assumed as the principal mechanism of toxicity of MCs, however recently it has been found that MC modulates PP2A activity not only by direct inhibition of its activity, but also by regulating its expression. Nevertheless the mechanisms of toxicity of MCs seem to be more complex to interpret than expected. The induction of some cellularmolecular mechanisms appears to be biphasic in time and concentration of MC and in most cases related with the intracellular ROS generation. These intracellular ROS levels cause oxidative stress which leads to changes in several markers of MC-LR-induced oxidative stress ultimately resulting in apoptosis or cell damage and also genotoxicity. MCs can also induce severe changes in the cytoskeleton elements: microfilaments, intermediate filaments and microtubules, which results in changes in the cytoskeleton architecture and cell viability. There are also indications that there are second messengers involved in MC-LR mediated cytotoxicity and apoptosis. Different congeners of these toxins induce different degrees of responses in the cell, assumed to be related with the capacity of toxin internalization, affinity towards PP1 and PP2A, and the ability to cause oxidative stress. MCs have also been implicated in neurotoxicity and in damages in reproductive organs. The regulation of transcription factors and proto-oncogenes by MC is the mode of action of MCs tumor promotion. This review summarizes mainly the findings from the last five years about the molecular mechanisms behind MC toxicity in animal cells.