Mechanism of Initiation of Liver Carcinogenesis by Dietary Imbalance

  • Amiya K. Ghoshal
  • Danny Ghazarian
  • Amit Ghoshal
  • Thomas Rushmore
  • Emmanuel Farber


The role of diet in the modulation of carcinogenic process is known for several years. However, most of the emphasis was on how different macro and micro-constituents of diet can alter the biology of the system with respect to different carcinogens and modify the carcinogenic potential of the latter either by enhancing or diminishing the carcinogenicity to different organs. Recently, we and two other laboratories1–5 have shown that about 50% of rats develop hepatocellular carcinoma when fed a diet which is devoid of choline and low in methionine (CD) without any added carcinogen. The role of choline deficiency as a promoter in the carcinogenic process has been established6–7. The recent demonstration that CD alone without any added carcinogens caused liver cancer strongly suggests that CD both initiates and promotes, i.e. it is a carcinogenic regimen. This observation raised a puzzling question as to how the absence of something can cause initiation. A hypothesis has been proposed8 based on the following observations: (a) early hepatic nuclear lipid peroxidation which occurs in choline deficiency9 is followed closely by (b) DNA alteration10 and (c) liver cell proliferation11. These may represent the chain of events leading to initiation, promotion and eventually to cancer in this model where no known carcinogen is added.


Lipid Peroxidation Orotic Acid Liver Carcinogenesis Liver Cell Necrosis Choline Deficient Diet 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    A. K. Ghoshal and E. Farber, Induction of liver cancer by a diet deficient in choline and methionine (CMD), Proc. Am. Assoc. Cancer Res. 24:98 (1983).Google Scholar
  2. 2.
    L. A. Poirier, Y. B. Mikol, K. Hoover and D. Creasia, Liver tumor formation in rats fed methyl-deficient amino acid-defined diets with and without diethylnitrosamine initiation, Proc. Am. Assoc. Cancer Res. 24:97 (1983).Google Scholar
  3. 3.
    Y. B. Mikol, K. L. Hoover, D. Creasia and L. A. Poirier, Hepatocarcinogenesis in rats fed methyl-deficient, amino acid defined diets, Carcinogenesis 4:1619 (1983).PubMedCrossRefGoogle Scholar
  4. 4.
    A. K. Ghoshal and E. Farber, The induction of liver cancer by dietary deficiency of choline and methionine without added carcinogens, Carcinogenesis 5:1367 (1984).PubMedCrossRefGoogle Scholar
  5. 5.
    S. Yokcvama, M. A. Sells, T. V. Reddy and B. Lombardi, Hepatocarcinogenesis and promoting action of a choline-devoid diet in the rat, Cancer Res. 45:2834 (1985).Google Scholar
  6. 6.
    M. A. Sells, S. L. Katyal, S. Sell, H. Shinozuka and B. Lombardi, Induction of foci of altered, γ-glutamyltranspeptidase-positive hepatocytes in carcinogen-treated rats fed a choline-deficient diet, Br. J. Cancer 40:274 (1979).PubMedCrossRefGoogle Scholar
  7. 7.
    B. Lombardi and H. Shinozuka, Enhancement of 2-acetylaminofluorene liver carcinogenesis in rats fed a cholinr-devoid diet, Int. J. Cancer 23:565 (1979).PubMedCrossRefGoogle Scholar
  8. 8.
    A. K. Ghoshal, D. S. R. Sarma and E. Farber, Ethionine in the analysis of the possible separate roles of methionine and choline deficiences in carcinogenesis, in: “Essential Nutrients in Carcinogenesis”, L. A. Poirier, P. M. Newberne, and M. W. Pariza, eds., Plenum Press, New York (1986)Google Scholar
  9. 9.
    T. H. Rushmore, Y. P. Lim, E. Farber and A. K. Ghoshal, Rapid lipid peroxidation in the nuclear fraction of rat liver induced by a diet deficient in choline and methionine, Cancer Lett. 24:251 (1984).PubMedCrossRefGoogle Scholar
  10. 10.
    T. H. Rushmore, E. Farber, A. K. Ghoshal, S. Parodi, M. Pala and M. Taningher, A choline-devoid diet, carcinogenic in the rat, induces DNA damage and repair, Carcinogenesis 7:1677 (1986).PubMedCrossRefGoogle Scholar
  11. 11.
    A. K. Ghoshal, M. Ahluwalia and E. Farber, The rapid induction of liver cell death in rats fed a choline-deficient methionir a-low diet, Am. J. Pathol. 113:309 (1983).PubMedGoogle Scholar
  12. 12.
    A. K. Ghoshal, T. H. Rushmore and E. Farber, Initiation of carcinogenesis by a dietary deficiency of choline in the absence of added carcinogens, Cancer Lett. 36:289 (1987).PubMedCrossRefGoogle Scholar
  13. 13.
    H. Tsuda, G. Lee and E. Farber, Induction of resistant hepatocytes as a new principle for a possible short-term in vivo test for carcinogens, Cancer Res. 40:1157 (1980).PubMedGoogle Scholar
  14. 14.
    D. B. Solt, E. Cayama, H. Tsuda, K. Enomoto, G. Lee and E. Farber, Promotion of liver cancer development by brief exposure to dietary 2-acetylaminofluorene plus partial hepatectomy or carbon tetrachloride, Cancer Res. 43:188 (1983).PubMedGoogle Scholar
  15. 15.
    D. B. Solt, A. Medline and E. Farber, Rapid emergence of carcinogeninduced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis, Am. J. Pathol. 88:595 (1977).PubMedGoogle Scholar
  16. 16.
    S. Inouye, Site-specific cleavage of double-strand DNA by hydroperoxide of linoleic acid, FEBS Lett. 172:231 (1984).PubMedCrossRefGoogle Scholar
  17. 17.
    T. J. Slaga, A. J. R. Klein-Szanto, L. L. Triplett, L. P. Yotti and J. E. Trosko, Skin tumor-promoting activity of bezoyl peroxide, a widely used free radical-generating compound, Science 213:1023 (1981).PubMedCrossRefGoogle Scholar
  18. 18.
    A. Benedetti, G. Malvaldi, R. Fulceri and M. Comporti, Loss of lipid peroxidation as a histochemical marker for preneoplastic hepatocellular foci in rats, Cancer Res. 44:5712 (1984).PubMedGoogle Scholar
  19. 19.
    H. Esterbauer, Aldehydic products of lipid peroxidation, in: “Free Radicals, Lipid Peroxidation and Cancer, D. C. H. McBrien and T. C. Slater, eds., Academic Press, London (1982).Google Scholar
  20. 20.
    E. K. Lai, P. B. McKay, T. Noguchi and K-L. Fong, In vivo spintrapping of trichloromethyl radicals formed from CCl4, Biochem. Pharmacol. 28:2231 (1979).PubMedCrossRefGoogle Scholar
  21. 21.
    A. K. Ghoshal, V. Subrahmanyan, T. H. Rushmore and E. Farber, The reversal of nuclear lipid peroxidation by a spin trap agent “PBN” in rats on a choline deficient diet, Proc. Am. Assoc. Cancer Res. 28:161 (1987).Google Scholar
  22. 22.
    A. Ghoshal, A.-K. Ghoshal, T. H. Rushmore and E. Farber, Glutathione and enzymes related to free radical metabolism in liver of rats fed a choline deficient diet, Proc. Am. Assoc. Cancer Res. 28:162 (1987).Google Scholar
  23. 23.
    A. Meister, Glutathione, in: “The Liver: Biology and Pathology”, L. A. Arias, H. Popper, B. Schachter, and E. A. Shefritz, eds., Raven Press, New York (1982).Google Scholar
  24. 24.
    A. Columbano, S. Rajalakshmi and D. S. R. Sarma, Requirement of cell proliferation for the induction of presumptive preneoplastic lesions in rat liver by a single dose of 1,2-dimethylhydrazine, Chem. Biol. Interactions 32:347 (1980).CrossRefGoogle Scholar
  25. 25.
    H. Shinozuka and B. Lombardi, Synergistic effect of a choline-devoid diet and phenobarbital in promoting the emergence of foci of γ-glutamyl-transpeptidase-positive hepatocytes in the liver of carcinogen treated rats, Cancer Res. 40:3846 (1980).PubMedGoogle Scholar
  26. 26.
    L. I. Giambarresi, S. L. Katyal and B. Lombardi, Promotion of liver carcinogenesis in the rat by a choline-devoid diet: Role of liver cell necrosis and regeneration, Br. J. Cancer 46:825 (1982).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Amiya K. Ghoshal
    • 1
  • Danny Ghazarian
    • 1
  • Amit Ghoshal
    • 1
  • Thomas Rushmore
    • 1
  • Emmanuel Farber
    • 1
  1. 1.Department of Pathology, Medical Sciences BuildingUniversity of TorontoTorontoCanada

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