Ultrastructure of the Liver in Response to Cyclophosphamide and Triterpenoids

  • 3 Accesses

Ultrastructural reorganization of liver cells after isolated injections of cyclophosphamide, betulonic acid or its β-alanylamide, and combined treatment with the cytostatic and each of the triterpenoids is studied. Cyclophosphamide causes significant ultrastructural changes in all intracellular compartments of hepatocytes. Both triterpenoids cause moderate cytotoxic and stimulatory effects on the liver cell populations (hepatocytes, sinusoidal endotheliocytes, and Kupffer cells), when used alone. The cytotoxic effect of betulonic acid manifests in modification of the fine structure of hepatocyte mitochondria, sequestration of glycogen, intensification of autophagic processes, emergence of necrobiotic changes in hepatocytes and endotheliocytes; betulonic acid amide actively modifies the mitochondrial fine structure (hypertrophic organelles, matrix rarefaction, uneven dilatation of cristae). The effects of combinations of cyclophosphamide with betulonic acid or its amide on liver are polytarget: the cytotoxic activity of the cytostatic is potentiated towards some cells, while in other cells the regeneratory reactions are stimulated. The common cytological cytoprotective effects of betulonic acid and its amide used alone and in combination with cytostatics include stimulation of the endocytotic (pinocytotic) activities of the cells and stimulation of intracellular regeneration processes in them.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA


  1. 1.

    Goldberg ED, Dygai AM, Sherstoboev EYu. Mechanisms of Local Regulation of Hematopoiesis in Cytostatic Myelosuppression. Tomsk, 2000. Russian.

  2. 2.

    Lushnikova EL, Molodykh OP, Nepomnyashchikh LM, Bakulina AA, Sorokina YA. Ultrastructurural picture of cyclophosphamide-induced damage to the liver. Bull. Exp. Biol. Med. 2011;151(6):751-756.

  3. 3.

    Lushnikova EL, Nepomnyashchikh LM, Tolstikova TG. Pathomorphology of Cardiomyocytes under the Action of Cyclophosphamide and Triterpenoids. Moscow, 2009. Russian.

  4. 4.

    Lushnikova EL, Tolstikova TG, Nepomnyashchikh LM, Klinnikova MG, Molodykh OP, Sviridov EA, Sorokina IV, Zhukova NA. Cardiomyocyte count in rat myocardium under the effect of antitumor agents cyclophosphamide and triterpenoids. Bull. Exp. Biol. Med. 2007;144(3):355-361.

  5. 5.

    Nepomnyashchikh LM, Molodykh OP, Lushnikova EL, Sorokina YA. Morphogenesis and histostereological analysis of hepatopathy induced by cyclophosphamide. Bull. Exp. Biol. Med. 2010;149(1):104-112.

  6. 6.

    Nikitin IG, Storzhakov GI. Drug-induced liver injury. Diseases of the Liver and Biliary Tract: A Guide for Doctors. Ivashkin VT, ed. Moscow, 2002. Russian.

  7. 7.

    Pal’tsev MA, Ivanov AA, Severin SE. Cell—Cell Interactions. Moscow, 2003. Russian.

  8. 8.

    Semenov DE, Zhukova NA, Bessergeneva EP, Sorokina IV, Baev DS, Glukhov BM, Nepomnyaschikh GI, Tolstikova TG. Effect of triterpene derivatives on the total hepatocyte count in the liver of rats with toxic hepatitis. Bull. Exp. Biol. Med. 2012;153(6):858-861.

  9. 9.

    Semenov DE, Zhukova NA, Ivanova EP, Sorokina IV, Baiev DS, Nepomnyashchikh GI, Tolstikova TG, Biryukova MS. Hepatoprotective properties of betulonic acid amide and heptral in toxic liver injury induced by carbon tetrachloride in combination with ethanol. Bull. Exp. Biol. Med. 201;158(3):336-341. doi:

  10. 10.

    Kawabata K, Kitamura K, Irie K, Naruse S, Matsuura T, Uemae T, Taira S, Ohigashi H, Murakami S, Takahashi M, Kaido Y, Kawakami B. Triterpenoids isolated from ziziphus jujuba enhance glucose uptake activity in skeletal muscle cells. J. Nutr. Sci. Vitaminol. (Tokyo). 2017;63(3):193-199.

  11. 11.

    Sorokina IV, Baev DS, Zhukova NA, Tolstikova TG, Antimonova AN, Petrenko NI, Shul’ts EE, Grigor’ev IA. Hepatoprotective activity of betulonic acid amides containing piperidine or pyrrolidine nitroxide moieties. Bioorg. Khim. 2013;39(6):749-752.

  12. 12.

    Sousa JLC, Freire CSR, Silvestre AJD, Silva AMS. Recent developments in the functionalization of betulinic acid and its natural analogues: a route to new bioactive compounds. Molecules. 2019;24(2). pii: E355. doi:

  13. 13.

    Yang SJ, Liu MC, Zhao Q, Hu DY, Xue W, Yang S. Synthesis and biological evaluation of betulonic acid derivatives as antitumor agents. Eur. J. Med. Chem. 2015;96:58-65. doi:

  14. 14.

    Yang S, Zhao Q, Xiang H, Liu M, Zhang Q, Xue W, Song B, Yang S. Antiproliferative activity and apoptosis-inducing mechanism of constituents from Toona sinensis on human cancer cells. Cancer Cell Int. 2013;13(1). ID 12. doi:

Download references

Author information

Correspondence to O. P. Molodykh.

Additional information

Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 168, No. 9, pp. 376-382, September, 2019

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Molodykh, O.P., Sorokina, I.V., Vinogradova, E.V. et al. Ultrastructure of the Liver in Response to Cyclophosphamide and Triterpenoids. Bull Exp Biol Med 168, 400–405 (2020).

Download citation

Key Words

  • hepatocytes
  • cyclophosphamide
  • triterpenoids
  • hepatotoxicity
  • ultrastructure