Comparison of protein phosphatase inhibitory activity and apparent toxicity of microcystins and related compounds

Two metabolites of microcystin-LR glutathione conjugate and, microcystin–cysteine conjugate, as well as microcystin-RR (MCRR) are less toxic than microcystin-LR (MCLR). In the present study, we investigated why these compounds are weakly toxic in comparison with MCLR, as the reason is still unknown and no systematic study has so far been carried out for a clarification of this issue. Although they showed almost the same inhibitory activity against protein phosphatases 1 and 2A as MCLR in vitro, the apparent toxicity of these three compounds by intratracheal administration to mice decreased to about 1/12 the level of MCLR at 100 μg/kg. An immunostaining study showed that these conjugates at a sublethal dose of 200 μg/kg were prominently observed in the intestine and kidney, whereas effective accumulation and bleeding were not found in the liver in spite of the larger dosage. As an explanation for these results, there may be two possibilities. First, the transport system to the liver might not function well, and second, transported toxins may be effectively eliminated by an appropriate system such as the GS-X (ATP-dependent glutathione S-conjugate exported) pump. It was concluded that the inhibitory activity against protein phosphatases is not always related to the apparent LD50 level, and that the appearance of toxicity by microcystins depends on the balance between accumulation and metabolism in the liver. [Copyright &y& Elsevier]