Promoting effect of citrulline in hepatocarcinogenesis: possible mechanism in hypercitrullinemia

Hepatology. 1990 May;11(5):819-23. doi: 10.1002/hep.1840110517.


Hypercitrullinemia (adult type), believed to be one of the hereditary urea cycle disorders, is known to be complicated by hepatocellular carcinoma at a high incidence (approximately 14%). We investigated the relationship between this hypercitrullinemia and hepatocarcinogenesis. After the addition of citrulline, incorporation of tritiated thymidine into primary cultured hepatocytes of adult rat increased in a dose-dependent fashion in the range of 0.1 to 5 mmol/L. The citrulline-added group also showed significant increase in ornithine and polyamine contents in hepatocytes. The incidence of epithelial cell foci in the in vivo-in vitro tumor promotion analyzing system significantly rose in the group maintained with 5 mmol/L citrulline and in the group maintained with 1.5 mmol/L phenobarbital. These findings suggest the possibility that citrulline has a promotion effect on hepatocyte proliferation and that at high concentrations it plays the role of a hepatocarcinogenesis promoter.

MeSH terms

  • Amino Acids / pharmacology
  • Animals
  • Biomechanical Phenomena
  • Carcinogens / pharmacology*
  • Cell Division / drug effects
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Citrulline / blood
  • Citrulline / pharmacology*
  • Liver / drug effects
  • Liver / pathology
  • Liver Neoplasms, Experimental / chemically induced*
  • Male
  • Polyamines / metabolism
  • Rats
  • Rats, Inbred Strains
  • Thymidine / metabolism


  • Amino Acids
  • Carcinogens
  • Polyamines
  • Citrulline
  • Thymidine