NODULARIN, A POTENT INHIBITOR OF PROTEIN PHOSPHATASE-1 AND PHOSPHATASE-2A, IS A NEW ENVIRONMENTAL CARCINOGEN IN MALE F344 RAT-LIVER

Nodularin and microcystin-1R are cyanobacterial toxins and environment al hazards, Nodularin inhibits protein phosphatases 1 and 2A with the same potency as does microcystin-1R, which has recently been identifie d 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 carci nogenesis experiment in rat liver initiated with diethylnitrosamine an d without partial hepatectomy revealed that nodularin stimulated gluta thione S-transferase placental form-positive foci in rat liver more ef fectively than did microcystin-1R, and that nodularin alone induced gl utathione S-transferase placental form-positive foci as well as did di ethylnitrosamine alone, Thus, nodularin itself is a new liver carcinog en, and microcystin-LR is a tumor promoter rather than a carcinogen. N odularin induced hyperphosphorylation of cytokeratin peptides 8 and 18 in primary cultured rat hepatocytes 20% more effectively than did mic rocystin-LR, suggesting that nodularin penetrates more easily into the hepatocytes than does microcystin-LR. Nodularin up-regulated inductio n of c-jun, jun-B,jun-D, c-fos,fos-B, and fra-1 mRNA transcripts in ra t liver after i.p. administration, and the accumulation of the mRNA tr anscripts was sustained for over 9 h after treatment, The environmenta l hazards of cyanobacterial toxins are discussed in relation to human primary liver cancer in Qidong county in the People's Republic of Chin a. Our results support this hypothesis and indicate the need for preve ntion measures against cyanobacterial toxins,