© 1993 Oxford University Press
research-article |
Cyclosporine stimulates hepatocyte proliferation and accelerates development of hepatocellular carcinomas in rats
Department of Pathology, University of Pittsburgh School of Medicine Pittsburgh, PA 15261, USA
1Department of Biology, Faculty of Science, Kyushu University Fukuoka 812, Japan
2To whom correspondence should be addressed
A recent study from our laboratory demonstrated that cyclo-sporine (CsA), a prototype immunosuppressant, enhanced the growth of carcinogen-induced enzyme altered foci in rat liver, suggesting that CsA may stimulate development of hepato-cellular carcinomas. In the present study, we examined (i) whether CsA accelerates development of hepatocellular carcinomas in experimental animals, (ii) whether CsA stimulates the proliferation of resting hepatocyte in vivo and (iii) whether CsA modulates the production of growth factors implicated in liver cell growth, hepatocyte growth factor (HGF), transforming growth factor a (TGF
) and transforming growth factor ß1 (TGFßß1). Foci of hepatocytes, positive for glutathione S-transferase placental form were induced in male F344 rats by a single dose of diethylnitros-amine followed by 7 weeks promotion by a choline-deficient diet. The animals were then divided in two groups, and subsequent development of hepatocellular carcinomas was compared in rats fed a basal diet or a basal diet containing 0.015% CsA. Development of hepatocellular carcinomas was accelerated in the rats maintained on a CsA diet. Feeding a CsA diet as the sole treatment, for 2, 4 and 10 weeks induced significant increases in liver weight, and resulted also in an enhanced incorporation by hepatocytes of 5-bromo-2-deoxy-uridine. Serum levels of glutamate-oxaloacetate transferase, glutamate-pyruvate transferase and lactic dehydrogenase were not altered by feeding a CsA diet. Northern Blot analyses of the expression of HGF, TGF and TGFß1 mRNAs in the liver showed similar patterns of expression between rats fed a basal diet and a CsA diet. The levels of HGF mRNA were not altered in the lungs and kidneys of rats fed a CsA diet. These results indicate that CsA stimulates rat liver cell proliferation in vivo without inducing liver cell necrosis, and that this effect may contribute to accelerated development of hepatocellular carcinomas in rats fed a CsA diet. As previously observed with BR 931, a hypolipidemic peroxisome proliferator, stimulation of liver cell growth by CsA did not entail changes in the production of HGF, TGF or TGFß1.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Domhan, M. Zeier, and A. Abdollahi Immunosuppressive therapy and post-transplant malignancy Nephrol. Dial. Transplant., April 1, 2009; 24(4): 1097 - 1103. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Duque, M. Fresno, and M. A. Iniguez Expression and Function of the Nuclear Factor of Activated T Cells in Colon Carcinoma Cells: INVOLVEMENT IN THE REGULATION OF CYCLOOXYGENASE-2 J. Biol. Chem., March 11, 2005; 280(10): 8686 - 8693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K L Hastings Assessment of immunosuppressant drug carcinogenicity: standard and alternative animal models Human and Experimental Toxicology, April 1, 2000; 19(4): 261 - 265. [Abstract] [PDF]
|
|
|
|
 |
|
 S. J. Provencher, C. Demers, M.-C. Bastien, J.-P. Villeneuve, and M. Gascon-Barré Effect of Cyclosporine A on Cytochrome P-450-Mediated Drug Metabolism in the Partially Hepatectomized Rat Drug Metab. Dispos., April 1, 1999; 27(4): 449 - 455. [Abstract] [Full Text]
|
|
|
|
 |
|
 H. C. Pitot The Progression of Neoplasia, Cell Replication, and Electromagnetic Fields International Journal of Toxicology, January 1, 1998; 17(3_suppl): 59 - 108. [PDF]
|
|