SUPPRESSION BY CAROTENOIDS OF MICROCYSTIN-INDUCED MORPHOLOGICAL-CHANGES IN MOUSE HEPATOCYTES

Microcystin-LR is a liver tumor promoter in the okadaic acid class, a group of potent inhibitors of protein phosphatases 1 and 2A. Because o f inhibition of protein phosphatases, microcystin-LR induces hyperphos phorylation of cellular proteins, including cytoskeletal proteins-cyto keratins 8 and 18-and causes morphological changes in mouse hepatocyte s in primary culture. We studied the effects of carotenoids to antagon ize microcystin-LR-induced morphological changes in hepatocytes. beta- carotene (100 nM to 100 mu M) suppressed the morphological changes ind uced by 100 nM microcystin-LR in a dose-dependent manner. Other carote noids tested exerted similar suppressive effects, although retinoids, such as all-trans retinol, all-trans retinoic acid, and 9-cis retinoic acid, were only weakly suppressive. The relative potency of the suppr ession correlated significantly with the number of conjugated double b onds in the trans configuration. beta-Carotene strongly suppressed the hyperphosphorylation of cellular proteins induced by microcystin-LR w ithout significant changes in the basal phosphorylation level. Other a ntioxidants, such as alpha-tacopherol, did not protect the cells again st microcystin-LR. Taken together, the antagonistic effects of caroten oids against microcystin-LR are difficult to explain by their antioxid ant or provitamin A activities. Suppression of the hyperphosphorylatio n of cellular proteins may be a novel mechanism by which carotenoids i nhibit tumor promotion.