Promoting effect of citrulline in hepatocarcinogenesis: possible mechanism in hypercitrullinemia.
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.
Nakayama
M
M
Third Department of Internal Medicine, Nara Medical University, Japan.
Okamoto
Y
Y
Morita
T
T
Matsumoto
M
M
Fukui
H
H
Nakano
H
H
Tsujii
T
T
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena; D002273:Carcinogens / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002956:Citrulline / Q000097:blood / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D011073:Polyamines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism
D000596:Amino Acids; D002273:Carcinogens; D011073:Polyamines; D002956:Citrulline; D013936:Thymidine