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Mycopathologia

, Volume 117, Issue 1–2, pp 73–78 | Cite as

In vitro toxicology of fumonisins and the mechanistic implications

  • William P. Norred
  • Elaine Wang
  • Hwansoo Yoo
  • Ronald T. Riley
  • Alfred H. MerrillJr.
Article

Abstract

The effects of fumonisins B1FB1, B2(FB{2}), and the backbone of fumonisin B1 remaining after hydrolysis of the tricarballylic groups with base (HFB1) on sphingolipid biosynthesis were studied in both primary rat hepatocytes and pig kidney epithelial cells (LLC-PK1). Fumonisins were potent inhibitors of sphingolipid biosynthesis in hepatocytes (IC50 of FB1=0.1 μM), but overt toxicity was not observed. In renal cells, fumonisins also inhibited sphingosine biosynthesis (IC50 for FB1=35 μM), and caused decreased cell proliferation as well. Higher doses (⩾70 μM) killed renal cells after exposure for 3 days. The inhibition of de novo sphingolipid biosynthesis was specific, and appeared to be at the site of ceramide synthase, which catalyzes the formation of dihydroceramide or ceramide by the addition of the amide-linked fatty acid to sphinganine or sphingosine. These results may account for the ability of fumonisins to cause equine leucoencephalomalacia and to promote tumor formation.

Key words

Fumonisins sphingolipids primary hepatocytes renal cells 

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References

  1. 1.
    Gelderblom WCA, Jaskiewicz K, Marasas WFO, Thiel PG, Horak RM, Vleggaar R, Kriek NPJ. Fumonisins — novel mycotoxins with cancer-promoting activity produced by Fusarium moniliforme. Appl Environ Microbiol 1988; 54: 1806–1811.Google Scholar
  2. 2.
    Bezuidenhout SC, Gelderblom WCA, Gorst-Allman CP, Horak RM, Marasas WFO, Spiteller G, Vleggaar R. Structure elucidation of the fumonisins, mycotoxins from Fusarium moniliforme. J Chem Soc, Chem Commun 1988; 743–745.Google Scholar
  3. 3.
    Booth C. The genus Fusarium. Kew, England: Commonwealth Mycological Institute, 1971.Google Scholar
  4. 4.
    Kellerman TS, Marasas WFO, Pienaar JG, Naude TW. A mycotoxicosis of Equidae caused by Fusarium moniliforme Sheldon. A preliminary communication. Onderstepoort J Vet Res 1972; 39: 205–208.Google Scholar
  5. 5.
    Haliburton JC, Vesonder RF, Lock TF, Buck WB. Equine leukoencephalomalacia (ELEM): a study of Fusarium moniliforme as an etiologic agent. Vet Hum Toxicol 1979; 21: 348–351.Google Scholar
  6. 6.
    Wilson BJ, Maronpot RR. Causative fungal agent of leucoencephalomalacia in equine animals. Veterinary Record 1971; 88: 484–486.Google Scholar
  7. 7.
    Marasas WFO, Kriek NPJ, Fincham JE, van Rensburg SJ. Primary liver cancer and oesophageal basal cell hyperplasia in rats caused by Fusarium moniliforme. Int J Cancer 1984; 34: 383–387.Google Scholar
  8. 8.
    Yang CS. Research on esophageal cancer in China: a review. Cancer Res 1980; 40: 2633–2644.Google Scholar
  9. 9.
    Li M, Lu S, Ji C, Wang Y, Wang M, Cheng S, Tian G. Experimental studies of the carcinogencity of fungus-contaminated food from Linxian county. In: Gelboin HV, ed. Genetic and environmental factors in experimental and human cancer. Tokyo: Japan Sci. Soc. Press, 1980; 139–148.Google Scholar
  10. 10.
    Cheng SJ, Jiang YZ, Li MH, Lo HZ. A mutagenic metabolite produced by Fusarium moniliforme isolated from Linxian county, China. Carcinogenesis 1985; 6: 903–905.Google Scholar
  11. 11.
    Marasas WFO, Wehner FC, van Rensburg SJ, Van Schalkwyk DJ. Mycoflora of corn produced in human esophageal cancer areas in Transkei, southern Africa. Phytopathology 1981; 71: 792–796.Google Scholar
  12. 12.
    Marasas WFO, Jaskiewicz K, Venter FS, Van Schalkwyk DJ. Fusarium moniliforme contamination of maize in oesophageal cancer areas in Transkei. S Afr Med J 1988; 74: 110–114.Google Scholar
  13. 13.
    Marasas WFO, Kellerman TS, Gelderblom WCA, Coetzer JAW, Thiel FG, van der Lugt JJ. Leukoencephalomalacia in a horse induced by fumonisin B1 isolated from Fusarium moniliforme. Onderstepoort J Vet Res 1988; 55: 197–203.Google Scholar
  14. 14.
    Kellerman TS, Marasas WFO, Thiel PG, Gelderblom WCA, Cawood M, Coetzer AW. Leucoencephalomalacia in two horses induced by oral dosing of fumonisin B1. Onderstepoort J Vet Res 1990; 57: 269–275.Google Scholar
  15. 15.
    Gelderblom WCA, Kriek NPJ, Marasas WFO, Thiel PG. Toxicity and carcinogenicity of the Fusarium moniliforme metabolite, fumonisin B1, in rats. Carcinogenesis 1991; 12: 1247–1251.Google Scholar
  16. 16.
    Wang E, Merrill AH, Norred WP, Bacon CW, Riley RT. Inhibition of sphingosine biosynthesis by fumonisins, mycotoxins produced by Fusarium moniliforme. FASEB 1991; 5: A1605.Google Scholar
  17. 17.
    Merrill AH, Jr. Cell regulation by sphingosine and more complex sphingolipids. J Bioenergetics Biomembranes 1991; 23: 83–104.Google Scholar
  18. 18.
    Voss KA, Norred WP, Plattner RD, Bacon CW. Hepatotoxicity and renal toxicity in rats of corn samples associated with field cases of equine leukoencephalomalacia. Fd Chem Toxicol 1989; 27: 89–96.Google Scholar
  19. 19.
    Wang E, Norred WP, Bacon CW, Riley RT, Merrill AH, Jr. Inhibition of sphingolipid biosynthesis by fumonisins: implications for diseases associated with Fusarium moniliforme. J Biol Chem 1991; 266: 14486–14490.Google Scholar
  20. 20.
    Yoo HS, Norred WP, Wang E, Merrill AH, Jr., Riley RT. Fumonisin inhibition of de novo sphingolipid biosynthesis and cytotoxicity are correlated in LLC-PK1 cells. Toxicol Appl Pharmacol 1992; in press.Google Scholar
  21. 21.
    Plattner RD, Norred WP, Bacon CW, Voss KA, Peterson R, Shackelford DD, Weisleder D. A method of detection of fumonisins in corn samples associated with field cases of equine leukoencephalomalacia. Mycologia 1990; 82: 698–702.Google Scholar
  22. 22.
    Yao Z, Vance DE. The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes. J Biol Chem 1988; 263: 2998–3004.Google Scholar
  23. 23.
    Riley RT, Norred WP, Dorner JW, Cole RJ. Increased accumulation of the lipophilic cation tetraphenylphosphonium+ by cyclopiazonic acid-treated renal epithelial cells. J Toxicol Environ Health 1985; 15: 779–788.Google Scholar
  24. 24.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 263–275.Google Scholar
  25. 25.
    Sirica AE, Pitot HC. Drug metabolism and effects of carcinogens in cultured hepatic cells. Pharm Rev 1980; 31: 205–228.Google Scholar
  26. 26.
    Steward AR, Dannan GA, Guzelian PS, Guengerich FP. Changes in the concentration of seven forms of cytochrome P-450 in primary cultures of adult rat hepatocytes. Mol Pharmacol 1985; 27: 125–132.Google Scholar
  27. 27.
    Merrill AH, Jr., Stevens VL. Modulation of protein kinase C and diverse cell functions by sphingosine — a pharmacologically interesting compound linking sphingolipids and signal transduction. Biochem Biophys Acta 1989; 1010: 131–139.Google Scholar
  28. 28.
    Hannun YA, Loomis CR, Merrill AH, Jr., Bell RM. Shingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J Biol Chem 1986; 261: 12604–12609.Google Scholar
  29. 29.
    Nishizuka Y. Studies and prospectives of the protein kinase C family for cellular regulation. Carcinogenesis 1989; 63: 1892–1903.Google Scholar
  30. 30.
    Norred WP, Bacon CW, Plattner RD, Vesonder RF. Differential cytotoxicity and mycotoxin content among isolates of Fusarium moniliforme. Mycopathologia 1991; 115: 37–43.Google Scholar
  31. 31.
    Norred WP, Plattner RD, Vesonder RF, Hayes PM, Bacon CW, Voss KA. Effect of Fusarium moniliforme metabolites on unscheduled DNA synthesis (UDS) in rat primary hepatocytes. Toxicologist 1990; 10: 165.Google Scholar

Copyright information

© Kluwer Academic Publishers 1992

Authors and Affiliations

  • William P. Norred
    • 1
  • Elaine Wang
    • 2
  • Hwansoo Yoo
    • 1
  • Ronald T. Riley
    • 1
  • Alfred H. MerrillJr.
    • 2
  1. 1.Toxicology and Mycotoxin Research Unit, Richard B. Russell Agricultural Research CenterUSDA/ARSAthensUSA
  2. 2.Department of BiochemistryEmory University School of MedicineAtlantaUSA

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