Protein phosphatase inhibition and in vivo hepatotoxicity of microcystins.

Administration of microcystin (MCYST)-YM or -LR (peptide hepatotoxins produced by the cyanobacterium Microcystis aeruginosa) to mice resulted in the inhibition of liver protein phosphatase 1 and 2A activity. In all cases significant inhibition preceded or accompanied clinical changes due to MCYST intoxication. Fifteen minutes after intraperitoneal injection of lethal doses of MCYST-YM protein phosphatase activity was already decreased to 44% of controls, and by 60 min was further decreased to 22% of controls. The inhibition was dose dependent: intraperitoneal injection with 84 nmol/kg of MCYST-YM and 48 nmol/kg of MCYST-LR were the minimum doses required for significant inhibition at 60 min. Pretreatment of mice with 200 mumol/kg of rifamycin prevented the inhibition of liver protein phosphatase. The inhibition was tissue specific, with none detected in the kidneys, an organ that, unlike the liver, does not accumulate MCYST. In contrast to MCYST intoxication, lethal doses of phalloidin, a peptide hepatotoxin that produces clinical and pathological changes similar to MCYST, did not cause any inhibition of protein phosphatases.