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 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. beta-carotene (100 nM to 100 microns) 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 the trans configuration. beta-carotene strongly suppressed the hyperphosphorylation of cellular proteins induced by microcystin-LR without significant changes in the basal phosphorylation level. Other antioxidants, such as alpha-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.
Matsushima-Nishiwaki
R
R
First Department of Internal Medicine, Gifu University School of Medicine, Japan.
Shidoji
Y
Y
Nishiwaki
S
S
Yamada
T
T
Moriwaki
H
H
Muto
Y
Y
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002338:Carotenoids / Q000494:pharmacology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019084:Fluorescent Antibody Technique, Indirect; D008099:Liver / Q000166:cytology* / Q000187:drug effects*; D014975:Lutein / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D052998:Microcystins; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D012176:Retinoids / Q000494:pharmacology; D019207:beta Carotene
D000975:Antioxidants; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D052998:Microcystins; D010456:Peptides, Cyclic; D012176:Retinoids; D019207:beta Carotene; D002338:Carotenoids; C078588:microcystin; D010749:Phosphoprotein Phosphatases; D014975:Lutein