Suppression by carotenoids of microtenoids of microcystin‐induced morphological changes in mouse hepatocytes

AbstractMicrocystin‐LR is a liver tumor promoter in the okadaic acid class, a group of potent inhibitors of protein phosphatases 1 and 2A. Because of inhibition of protein phosphatases, microcystin‐LR induces hyperphosphorylation of cellular proteins, including cytoskeletal proteins—cytokeratins 8 and 18—and causes morphological changes in mouse hepatocytes in primary culture. We studied the effects of carotenoids to antagonize microcystin‐LR‐induced morphological changes in hepatocytes. β‐Carotene (100 nM to 100 μM), suppressed the morphological changes induced by 100 nM microcystin‐LR in a dose‐dependent manner. Other carotenoids 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 suppression correlated significantly with the number of conjugated double bonds in thetrans configuration. β‐Carotene strongly suppressed the hyperphosphorylation of cellular proteins induced by microcystin‐LR without significant changes in the basal phosphorylation level. Other antioxidants, such as α‐tocopherol, did not protect the cells against microcystin‐LR. Taken together, the antagonistic effects of carotenoids against microcystin‐LR are difficult to explain by their antioxidant or provitamin A activities. Suppression of the hyperphosphorylation of cellular proteins may be a novel mechanism by which carotenoids inhibit tumor promotion.