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Liver tumor promotion by the cyanobacterial cyclic peptide toxin microcystin-LR

  • Rie Nishiwaki-Matsushima
  • Tetsuya Ohta
  • Shinji Nishiwaki
  • Masami Suganuma
  • Kiyomi Kohyama
  • Takatoshi Ishikawa
  • Wayne W. Carmichael
  • Hirota Fujiki
Original Papers Experimental Oncology

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.

Key words

Microcystin Tumor promoter Protein phosphatase 

Abbreviations

DEN

diethylnitrosamine

DMBA

7,12-dimethylbenz[a]anthracene

GST-P

glutathioneS-transferase placental form

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References

  1. 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] 5:345–361Google Scholar
  2. Blair PC, Popp JA, Bryant-Varela BJ, Thompson MB (1991) Promotion of hepatocellular foci in female rats by chenodeoxycholic acid. Carcinogenesis 12:59–63Google Scholar
  3. 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 1:2311–2318Google Scholar
  4. 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 1:2747–2748Google Scholar
  5. Carmichael WW (1988) Toxins of freshwater algae. In: Tu AT (ed) Handbook of natural toxins, vol 3. Dekker, New York, pp 121–147Google Scholar
  6. 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 26:971–973Google Scholar
  7. 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 54:2257–2263Google Scholar
  8. Eriksson JE, Grönberg L, Nygard S, Slotte JP, Meriluoto JAO (1990) Hepatocellular uptake of3H-dihydro microcystin-LR, a cyclic peptide toxin. Biochim Biophys Acta 1025:60–66Google Scholar
  9. Falconer IR (1991) Tumor promotion and liver injury caused by oral consumption of cyanobacteria. Environ Toxicol Water Quality 6:177–184Google Scholar
  10. Farber E, Solt D (1978) A new liver model for the study of promotion. In: Slaga TJ, Sivak A, Boutwell RK (eds) Carcinogenesis 2:443–451Google Scholar
  11. 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 2:184–187Google Scholar
  12. 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 337–350Google Scholar
  13. 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 48:1415–1420Google Scholar
  14. 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 29:577–580Google Scholar
  15. 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 71:832–842Google Scholar
  16. 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 24:865–873Google Scholar
  17. 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 171:867–874Google Scholar
  18. 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 55:6135–6139Google Scholar
  19. Peraino C, Fry RJM, Staffeldt E (1971) Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res 31:1506–1512Google Scholar
  20. 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 110:8557–8558Google Scholar
  21. 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 75:199–202Google Scholar
  22. 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 82:3964–3968Google Scholar
  23. 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 7:99–104Google Scholar
  24. Solt D, Farber E (1976) New principle for the analysis of chemical carcinogenesis. Nature 263:701–703Google Scholar
  25. 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 85:1768–1771Google Scholar
  26. Watanabe MF, Oishi S, Harada K-I, Matsuura K, Kawai H, Suzuki M (1988) Toxins contained inMicrocystis species of cyanobacteria (blue-green algae). Toxicon 26:1017–1025Google Scholar
  27. 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 116:609–614Google Scholar
  28. 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 30–37Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Rie Nishiwaki-Matsushima
    • 1
  • Tetsuya Ohta
    • 1
  • Shinji Nishiwaki
    • 1
  • Masami Suganuma
    • 1
  • Kiyomi Kohyama
    • 2
  • Takatoshi Ishikawa
    • 3
  • Wayne W. Carmichael
    • 4
  • Hirota Fujiki
    • 1
  1. 1.Cancer Prevention DivisionNational Cancer Center Research InstituteTokyoJapan
  2. 2.Department of Experimental PathologyCancer InstituteTokyoJapan
  3. 3.Department of Pathology, Faculty of MedicineTokyo UniversityTokyoJapan
  4. 4.Department of Biological SciencesWright State UniversityDaytonUSA

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