Hepatic toxicity and persistence of ser/thr protein phosphatase inhibitionby microcystin in the little skate Raja erinacea

Microcystin-induced ser/thr protein phosphatase (PP) inhibition and toxicit y were examined in the little skate (Raja erinacea), an evolutionarily prim itive marine vertebrate. As in mammals, PP inhibition and toxicity were exc lusively hepatocellular, but were much more persistent in the skate. A dose of 63 mu g/kg given iv to adult male skates resulted in the near complete inhibition of hepatic PP activity at 24 h. PP activity was still 95% inhibi ted 7 days after dosing in skates given 125 mu g/kg microcystin. Mortality occurred at doses of 500 mu g/kg or more. Hepatic lesions were only seen in animals with fully inhibited PP activity in liver. The histological change s seen at 125 mu g/kg were mild periportal inflammatory changes increasing in severity together with hepatocyte necrosis at higher doses of microcysti n. Microcystin persisted and could be detected in plasma up to 7 days after dosing. This finding shows that, in the skate, as in mammals, the liver is the only organ capable of uptake of microcystin, since there was no signif icant inhibition of PP activity in the rectal gland and small decreases in PP activity of the kidney that were not time or dose dependent. In vitro mi crocystin caused dose-dependent inhibition of PP activity in isolated skate hepatocytes, while it was without effect in cultured rectal glands. Uptake of microcystin and the accompanying inhibition of PP activity in skate hep atocytes was prevented by the addition of a series of organic dyes and bile acids. The spectrum of inhibitors of microcystin uptake in skate is simila r to that seen in the rat, indicating common features of the carrier(s) in these diverse species. (C) 1999 Academic Press.