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Nodularin, a Potent Inhibitor of Protein Phosphatases 1 and 2A, Is a New Environmental Carcinogen in Male F344 Rat Liver¹

Saitama Cancer Center Research Institute, 818 Komuro, Ina, Kitaadachi-gun, 362 Saitama, Japan [T. O., E. S., N. I., A. K., M. S., R. N., H. F.]; Aichi Cancer Center Research Institute, Nagoya 464, Japan [M. T.]; Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892 [S-J. K.]; and Department of Biological Sciences, Wright State University, Dayton, Ohio 45435 [W. W. C.]

Nodularin and microcystin-LR are cyanobacterial toxins and environmental hazards. Nodularin inhibits protein phosphatases 1 and 2A with the same potency as does microcystin-LR, which has recently been identified as a potent tumor promoter in rat liver. Our results suggested that nodularin is also a new tumor promoter in rat liver. A two-stage carcinogenesis experiment in rat liver initiated with diethylnitrosamine and without partial hepatectomy revealed that nodularin stimulated glutathione S-transferase placental form-positive foci in rat liver more effectively than did microcystin-LR, and that nodularin alone induced glutathione S-transferase placental form-positive foci as well as did diethylnitrosamine alone. Thus, nodularin itself is a new liver carcinogen, and microcystin-LR is a tumor promoter rather than a carcinogen. Nodularin induced hyperphosphorylation of cytokeratin peptides 8 and 18 in primary cultured rat hepatocytes 20% more effectively than did microcystin-LR, suggesting that nodularin penetrates more easily into the hepatocytes than does microcystin-LR. Nodularin up-regulated induction of c-jun, jun-B, jun-D, c-fos, fos-B, and fra-1 mRNA transcripts in rat liver after i.p. administration, and the accumulation of the mRNA transcripts was sustained for over 9 h after treatment. The environmental hazards of cyanobacterial toxins are discussed in relation to human primary liver cancer in Qidong county in the People's Republic of China. Our results support this hypothesis and indicate the need for prevention measures against cyanobacterial toxins.

¹ This work was supported in part by Grants-in-Aid for Cancer Research, Overseas Scientific Research Program (Cancer Program) from the Ministry of Education, Science and Culture and a grant from the Ministry of Health and Welfare for a Comprehensive 10-Year Strategy for Cancer Control, Japan, and grants from the Foundation for Promotion of Cancer Research, the Princess Takamatsu Cancer Research Fund, the Smoking Research Fund, the Uehara Memorial Life Science Foundation, M. O. A. Health Science Foundation, Suzuken Memorial Foundation, and the Asahi Glass Foundation.

² Present address: Mitsubishi Chemical Corporation Research Center, Aoba-ku, Yokohama 227, Japan.

³ Present address: First Department of Internal Medicine, Gifu University School of Medicine, Gifu 500, Japan.

⁴ To whom correspondence should be addressed.

Received 7/ 6/94. Accepted 10/17/94.

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