The lesion caused by microcystin-LR in the liver of the rat. Is it a model for apoptosis in vivo in the liver?

Several well-known inhibitors of the protein phosphatases 1 and 2A, including microcystins, have been shown to induce apoptosis in vitro. Microcystin-LR, which is hydrophilic and does not readily gain access to cells, is specifically toxic to liver cells when transported by the plasma membrane bile acid carrier. A single dose of microcystin-LR given intravenously to rats, at levels of 20-200 μg kg results in extensive loss of hepatocytes from the periacinar region within 15 min. Affected hepatocytes became detached from each other and rounded up, but nuclear changes characteristic of apoptosis were absent. A typical perivenular fibrosis was present by 48 h. These findings are consistent with recent in vitro studies that indicate that, where altered cytoplasmic protein phosphorylation is associated with apoptosis-like cell death, morphological changes may vary depending on the nature and progress of the modified protein phosphorylation and may exclude nuclear and other changes usually considered to be characteristic of apoptosis. Cantharidic acid, a lipophilic protein phosphatase 2A inhibitor dosed at 10 mg kg, had a similar effect on the hepatic parenchyma, but this was not zonally distributed as for microcystin-LR. With both compounds, contiguous hepatocytes became readily detached from one another, allowing the perfusion fluid to track at random through the liver as the sinusoidal channels appeared to lose their integrity. The lesion is apparently characteristic of this kind of protein phosphatase inhibitor in the liver. For comparison, single intravenous doses of the pyrrolizidine alkaloid monocrotaline at 50 mg kg and the protein synthesis inhibitor cycloheximide at 1.5 mg kg, respectively, have no such effects but cause up to 1% apoptosis of hepatocytes. Although monocrotaline at higher doses also causes hepatocellular necrosis, no such lesion occurs with cycloheximide. With the latter compound, the liver returned to normal within 48 h. Cycloheximide rather than microcystin-LR is thus a more appropriate compound for the induction of apoptosis in the liver.