Summary
Certain waterblooms of toxic cyanobacteria (blue-green algae) are a health threat because of their production of toxic peptides, termed microcystins, which cause liver damage in wild and domesticated animals. The most widely studied microcystin is microcystin-LR, a heptapeptide containing the twol-amino acids, leucine and arginine. The inhibition of protein phosphatase type 1 and type 2A activities by microcystin-LR is similar to that of the known protein phosphatase inhibitor and tumor promoter okadaic acid. We show in this report that microcystin-LR, applied below the acute toxicity level, dose-dependently increases the number and percentage area of positive foci for the placental form of glutathioneS-transferase in rat liver, which was initiated with diethylnitrosamine. The result was obtained independently through two animal experiments. This observation indicates that microcystin-LR is a new liver tumor promoter mediated through inhibition of protein phosphatase type 1 and type 2A activities. This provides further evidence that the okadaic acid pathway is a general mechanism of tumor promotion in various organs, such as mouse skin, rat glandular stomach and rat liver.
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Abbreviations
- DEN:
-
diethylnitrosamine
- DMBA:
-
7,12-dimethylbenz[a]anthracene
- GST-P:
-
glutathioneS-transferase placental form
References
Beasley VR, Cook WO, Dahlem AM, Hooser SB, Lovell RA, Valentine WM (1989) Algae intoxication in livestock and waterfowl. Vet Clin North AM [Food Anim Pract] 5:345–361
Blair PC, Popp JA, Bryant-Varela BJ, Thompson MB (1991) Promotion of hepatocellular foci in female rats by chenodeoxycholic acid. Carcinogenesis 12:59–63
Botes DP, Tuinman AA, Wessels PL, Vijoen CC, Kruger H, Williams DH, Santikarn S, Smith RJ, Hammond SJ (1984) The structure of cyanoginosin-LA, a cyclic heptapeptide toxin from the cyanobacteriumMicrocystis aeruginosa. J Chem Soc Perkin Trans 1:2311–2318
Botes DP, Wessels PL, Kruger H, Runnegar MTC, Santikarn S, Smith RJ, Barna JCJ, Williams DH (1985) Structural studies on cyanoginocins-LR,-YR,-YA, and-YM, peptide toxins fromMicrocystis aeruginosa. J Chem Soc Perkin Trans 1:2747–2748
Carmichael WW (1988) Toxins of freshwater algae. In: Tu AT (ed) Handbook of natural toxins, vol 3. Dekker, New York, pp 121–147
Carmichael WW, Krishnamurthy T, Beasley V, Min-Juan Y, Bunner DL, Moore RE, Eloff JN, Rinehart K, Falconer I, Runnegar M, Gorham P, Skulberg OM, Harada K-I, 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
Eriksson JE, Grönberg L, Nygard S, Slotte JP, Meriluoto JAO (1990) Hepatocellular uptake of3H-dihydro microcystin-LR, a cyclic peptide toxin. Biochim Biophys Acta 1025:60–66
Falconer IR (1991) Tumor promotion and liver injury caused by oral consumption of cyanobacteria. Environ Toxicol Water Quality 6:177–184
Farber E, Solt D (1978) A new liver model for the study of promotion. In: Slaga TJ, Sivak A, Boutwell RK (eds) Carcinogenesis 2:443–451
Fujiki H, Suganuma M, Yoshizawa S, Kanazawa H, Sugimura T, Manam S, Kahn SM, Jiang W, Hoshina S, Weinstein IB (1989) Codon 61 mutations in the c-Harvey-ras gene in mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene plus okadaic acid class tumor promotors. Mol Carcinogenesis 2:184–187
Fujiki H, Suganuma M, Nishiwaki S, Yoshizawa S, Yatsunami J, Matsushima R, Furuya H, Okabe S, Matsunaga S, Sugimura T (1992) Specific mechanistic aspects of animal tumor promoters: The okadaic acid pathway. In: D'Amato R, Slaga TJ, Farland W, Henry C (eds) Relevance of animal studies to the evaluation of human cancer risk, Wiley, New York, pp 337–350
Galey FD, Beasley VR, Carmichael WW, Kleppe G, Hooser SB, Haschek WM (1987) Blue-green algae (Microcystis aeruginosa) hepatotoxicosis in dairy cows. Am J Vet Res 48:1415–1420
Hsu SM, Raine L, Fanger H (1981) Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabelled antibody PAP procedures. J Histochem Cytochem 29:577–580
Ito N, Tatematsu M, Nakanishi K, Hasegawa R, Takano T, Imaida K, Ogiso T (1980) The effects of various chemicals on the development of hyperplastic liver nodules in hepatectomized rats treated withN-nitrosodiethylamine orN-2-fluorenylacetamide. Gann 71:832–842
Krishnamurthy T, Carmichael WW, Sarver EW (1986) Toxic peptides from freshwater cyanobacteria (blue-green algae): I. Isolation, purification and characterization of peptides fromMicrocystis aeruginosa andAnabena flos-aque. Toxicon 24:865–873
Matsushima R, Yoshizawa S, Watanabe MF, Harada K-I, Furusawa M, Carmichael WW, Fujiki H (1990) In vitro and in vivo effects of protein phosphatase inhibitors, microcystins and nodularin, on mouse skin and fibroblasts. Biochem Biophys Res Commun 171:867–874
Namikoshi M, Rinehart KL, Sakai R, Sivonen K, Carmichael WW (1990) Structures of three new cyclic heptapeptide hepatotoxins produced by the cyanobacterium (blue-green alga)Nostoc sp. strain 152. J Org Chem 55:6135–6139
Peraino C, Fry RJM, Staffeldt E (1971) Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res 31:1506–1512
Rinehart KL, Harada K-I, Namikoshi M, Chen C, Harvis CA, Munro MHG, Blunt JW, Mulligan PE, Beasley VR, Dahlem AM, Carmichael WW (1988) Nodularin, microcystin, and the configuration of Adda. J Am Chem Soc 110:8557–8558
Sato K, Kitahara A, Satoh K, Ishikawa T, Tatematsu M, Ito N (1984) The placental form of glutathioneS-transferase as a new marker protein for preneoplasia in rat chemical hepatocarcinogenesis. Gann 75:199–202
Satoh K, Kitahara A, Soma Y, Inaba Y, Hatayama I, Sato K (1985) Purification, induction and distribution of placental glutathione transferase: a new marker enzyme for preneoplastic cells in the rat chemical hepato carcinogenesis. Proc Natl Acad Sci USA 82:3964–3968
Schulte-Hermann R, Schuppler J, Ohde G, Timmermann-Trosiener I (1982) Effect of tumor promoters on proliferation of putative preneoplastic cells in rat liver. In: Hecker E, Fusenig NE, Kunz W, Marks F, Thielmann HW (eds) Carcinogenesis 7:99–104
Solt D, Farber E (1976) New principle for the analysis of chemical carcinogenesis. Nature 263:701–703
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. Proc Natl Acad Sci USA 85:1768–1771
Watanabe MF, Oishi S, Harada K-I, Matsuura K, Kawai H, Suzuki M (1988) Toxins contained inMicrocystis species of cyanobacteria (blue-green algae). Toxicon 26:1017–1025
Yoshizawa S, Matsushima R, Watanabe MF, Harada K-I, Ichihara A, Carmichael WW, Fujiki H (1990) Inhibition of protein phosphatases by microcystin and nodularin associated with hepatotoxicity. J Cancer Res Clin Oncol 116:609–614
Yu S-Z (1989) Drinking water and primary liver cancer. In: Tang ZY, Wu MC, Xia SS (eds) Primary liver cancer. China Academic Publishers, Springer, Berlin Heidelberg New York, pp 30–37
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Nishiwaki-Matsushima, R., Ohta, T., Nishiwaki, S. et al. Liver tumor promotion by the cyanobacterial cyclic peptide toxin microcystin-LR. J Cancer Res Clin Oncol 118, 420–424 (1992). https://doi.org/10.1007/BF01629424
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DOI: https://doi.org/10.1007/BF01629424