Report No FR0493/DoE 372

Nov 1994


Mycrocystin-LR appears to exert its toxic effects on liver by inhibition of protein phosphatases 1 and 2A. Okadaic acid, a toxin found in the marine environment is also a potent inhibitor of these groups of enzymes but has been shown to promote tumours in mouse skin initiated by other carcinogens. The inhibition of protein phosphatases is a possible mechanism of tumour promotion and therefore microcystin-LR is a suspected tumour promoter.

A number of well established tumour promoters have been shown to inhibit inter-cellular communication through gap junctions. This is probably important as a stage in tumour promotion, by removing the inhibitory influence of other cells on cell multiplication.

In order to assess the activity of microcystin-LR and okadaic acid, their ability to inhibit gap junction inter-cellular communication (GJIC) in hepatocytes and epithelial cells in vitro was measured. Okadaic acid did not inhibit GJIC in either hepatocytes or epithelial cells up to cytotoxic doses. Microcystin-LR induced significant inhibition in hepatocytes in a dose-related fashion but not in epithelial cells. This is in accordance with its recorded specificity for the liver.

The data from this preliminary study indicate that hepatocyte GJIC is very sensitive to the effects of microcystin-LR. This technique, in conjunction with measurement of protein phosphatase inhibition, could be used to investigate the concentrations at which a threshold is apparent, whether the effect is reversible, and whether the cells are so disabled that they cannot recover, and are therefore unable to grow into tumours. These data would provide an aid in the risk assessment of possible tumour promotion by microcystin-LR.

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