Related Experiment Videos
Protein phosphatase inhibition and in vivo hepatotoxicity of microcystins
M T Runnegar1, S Kong, N Berndt
1Department of Medicine, Children's Hospital, Los Angeles, California.
Abstract:
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.
Insights
Microcystins (MCYST) are cyanobacterial toxins that inhibit liver protein phosphatase activity in mice. This inhibition occurs before clinical signs of MCYST intoxication and is dose-dependent.
Area of Science:
- Toxicology
- Biochemistry
- Environmental Health
Background:
- Cyanobacteria, such as Microcystis aeruginosa, produce peptide hepatotoxins known as microcystins (MCYST).
- MCYSTs pose a significant risk to environmental and public health due to their toxicity.
Purpose of the Study:
- To investigate the effect of MCYST-YM and MCYST-LR on liver protein phosphatase activity in mice.
- To determine the relationship between MCYST intoxication, clinical signs, and protein phosphatase inhibition.
Main Methods:
- Administration of MCYST-YM and MCYST-LR to mice via intraperitoneal injection.
- Measurement of liver protein phosphatase 1 and 2A activity at various time points post-injection.
- Dose-response assessment and tissue-specific analysis (liver vs. kidneys).
- Investigation of the effect of rifamycin pretreatment on MCYST-induced inhibition.
Main Results:
- MCYST-YM and MCYST-LR administration significantly inhibited liver protein phosphatase 1 and 2A activity in mice.
- Inhibition of protein phosphatase activity preceded or coincided with clinical signs of MCYST intoxication.
- The inhibition was dose-dependent, with specific minimum doses required for significant effect.
- Rifamycin pretreatment prevented the inhibition of liver protein phosphatase.
- Inhibition was liver-specific, with no effect observed in kidneys.
Conclusions:
- MCYSTs exert their toxicity by inhibiting crucial liver protein phosphatases.
- The timing of phosphatase inhibition suggests a direct role in the pathogenesis of MCYST intoxication.
- The liver-specific accumulation of MCYST correlates with the tissue-specific inhibition of protein phosphatases.