Summary
Microcystins and nodularin, isolated from toxic blue-green algae, are hepatotoxic monocyclic polypeptides. Both microcystins and nodularin inhibited in vitro protein phosphatase activity present in a cytosolic fraction of mouse liver, bound to the okadaic acid receptors, protein phosphatases 1 and 2A, and thus resulted in the increase of phosphoproteins; this was referred to as the apparent “activation” of protein kinases. Their concentrations causing 50% of the maximal effects are comparable to that of okadaic acid, a potent protein phosphatase inhibitor and a potent tumor promoter, in the nanomolar range of concentration. The increase of phosphoproteins was observed in rat primary cultured hepatocytes and was subsequently associated with morphological changes, which appeared to be a step in the process of hepatotoxicity. The well-known hepatotoxic compounds,α-amanitin and phalloidin, did not show any effects similar to those of microcystins, nodularin and okadaic acid. It is suggested that the hepatotoxicity of microcystins and nodularin may result from inhibition of protein phosphatases and the increase of phosphoproteins.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bialojan C, Takai A (1988) Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Biochem J 256:283–290
Botes DP, Tuinman AA, Wessles PL, Viljoen CC, Kruger H (1984) The structure of cyanoginosin-LA, a cyclic heptapeptide toxin from the cyanobacteriumMicrocystis aeruginosa. J Chem Soc Perkin Trans 1:2311–2318
Carmichael WW (1988) Toxins of fresh water cyanobacteria. In: Tu A (ed) Handbook of natural toxins: vol 3. Dekker, New York, pp 121–147
Carmichael WW, Mahmood NA (1984) The structure of cyanoginosin-LA, a cyclic heptapeptide toxin from the cyanobacteriumMicrocystis aeruginosa. In: Ragelis EP (ed) Seafood toxins. American Chemical Society, Washington, pp 377–389
Carmichael WW, Beasley V, Bunner DL, Eloff JN, Falconer I, Gorham P, Harada KI, Krishnamurthy T, Min-Juan Y, Moore RE, Rinehart KL, Runnegar M, Skulberg OM, Watanabe M (1988a) Naming of cyclic heptapeptide toxins of cyanobacteria (blue-green algae). Toxicon 26:971–973
Carmichael WW, Eschedor JT, Patterson GML, Moore RE (1988b) Toxicity and partial structure of a hepatotoxic peptide produced by the cyanobacteriumNodularia spumigena Mertens emend. L575 from New Zealand. Appl Environ Microbiol 54:2257–2263
Francis G (1878) Poisonous Australian lake. Nature 18:11–12
Fry JR, Jones CA, Wiebkin P, Belleman P, Bgidges JW (1976) The enzymatic isolation of adult rat hepatocytes in a functional viable state. Anal Biochem 71:341–350
Harada KI, Matsuura K, Suzuki M, Oka H, Watanabe MF, Oishi S, Dahlem AM, Beasley VR, Carmichael WW (1988) Chemical analysis of toxic peptides from cyanobacteria by reversed phase high performance liquid chromatography. J Chromatogr 448:275–283
Hescheler J, Mieskes G, Rüegg JC, Takai A, Trautwein W (1988) Effects of a protein phosphatase inhibitor, okadaic acid, on membrane currents of isolated guinea-pig cardiac myocytes. Pflügers Arch ges Physiol 412:248–252
Howard RB, Lee JC, Pesch LA (1973) The fine structure potassium content, and respiratory activity of isolated rat liver parenchymal cells prepared by improved enzymatic techniques. J Cell Biol 57:642–658
Rinehart KL, Harada K, Namikoshi M, Chen C, Harvis CA, Munro MHG, Blunt JW, Mulligan PE, Beasley VR, Dahlem M, Carmichael WW (1988) Nodularin, microcystin, and the configuration of Adda. J Am Chem Soc 110:8557–8558
Sassa T, Richter WW, Uda N, Suganuma M, Suguri H, Yoshizawa S, Hirota M, Fujiki H (1989) Apparent “activation” of protein kinases by okadaic acid class tumor promoters. Biochem Biophys Res Commun 159:939–944
Scatchard G (1949) The attractions of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672
Slatkin DN, Stoner RD, Adams WH, Kycia JH, Siegelman HW (1983) Atypical pulmonary thrombosis caused by toxic cyanobacterial peptide. Science 220:1983–1985
Suganuma M, Fujiki H, Suguri H, Yoshizawa S, Hirota M, Nakayasu M, Ojika M, Wakamatsu K, Yamada K, Sugimura T (1988) Okadaic acid: An additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter in mouse skin. Proc Natl Acad Sci USA 85:1768–1771
Suganuma M, Suttajit M, Suguri H, Ojika M, Yamada K, Fujiki H (1989) Specific binding of okadaic acid, a new tumor promoter in mouse skin. FEBS Lett 250:615–618
Suganuma M, Fujiki H, Suguri HF, Yoshizawa S, Yasumoto S, Kato Y, Fusetani N, Sugimura T (1990) Calyculin A, an inhibitor of protein phosphatases, a potent tumor promoter on CD-1 mouse skin. Cancer Res 50:3521–3525
Tachibana T, Scheuer PJ, Tsukitani Y, Kikuchi H, Van Engen D, Clardy J, Gopichard Y, Schmitz FJ (1981) Okadaic acid, a cytotoxic polyether from two marine sponges of theGenus Halichondria. J Am Chem Soc 103:2471–2472
Tanaka K, Sato M, Tomita Y, Ichihara A (1978) Biochemical studies on liver functions in primary cultured hepatocytes of adult rats. J Biochem (Tokyo) 84:937–946
Watanabe MF, Ohishi S, Harada KI, Matsuura K, Kawai H, Suzuki M (1988) Toxins contained inMicrocystis species of cyanobacteria (blue-green algae) Toxicon 26:1017–1025
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yoshizawa, S., Matsushima, R., Watanabe, M.F. et al. Inhibition of protein phosphatases by microcystis and nodularin associated with hepatotoxicity. J Cancer Res Clin Oncol 116, 609–614 (1990). https://doi.org/10.1007/BF01637082
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01637082