Inhibition by interferon alpha-2b of rat liver regeneration: effect on ornithine decarboxylase and total protein synthesis.
Polyamines are key factors in macromolecule synthesis during liver regeneration. It has been postulated that interferon-alpha (IFNalpha) decreases putrescine levels in regenerating liver by inhibiting ornithine decarboxylase (ODC) activity, the main enzyme in polyamine biosynthesis. In the present study, we analysed the effects of a pharmacological dose of IFNalpha on polyamine and ODC levels during the regenerative process following partial hepatectomy in rats. Synthesis of ODC by isolated hepatocytes from IFN-treated rats with regenerating livers was also assessed. Furthermore, we investigated the effect of IFNalpha-2b on DNA and total protein synthesis in 24-hr regenerating livers. No effect on DNA synthesis was observed at the dose of IFNalpha-2b used, but total protein synthesis decreased significantly in IFNalpha-2b-treated rats undergoing liver regeneration (7.0 +/- 2.0 and 12.1 +/- 1.7%. min(-1) in hepatectomized rats treated with IFNalpha-2b and saline, respectively). ODC levels were also reduced significantly (by 50%) in hepatectomized rats treated with IFNalpha-2b versus saline. In parallel with the ODC decrease, the concentrations of putrescine and spermidine (63 +/- 25 vs 101 +/- 15 nmol/g liver and 1.08 +/- 0.35 vs 2.14 +/- 0.22 micromol/g liver, respectively, in IFNalpha-2b- and saline-treated hepatectomized rats) showed similar, significant diminutions. Moreover, the incorporation of [35S]methionine into ODC was decreased dramatically in isolated hepatocytes from IFNalpha-2b-treated hepatectomized rats 12 hr after surgery. In conclusion, the protein synthesis rate in regenerating liver was impaired by therapeutic doses of IFNalpha-2b. In addition, the results presented in this study suggest that IFNalpha-2b negatively regulates ODC synthesis, causing a reduction in polyamine levels during liver regeneration.
Favre
C
C
Institute of Experimental Physiology, National Council of Scientific and Technical Research, Faculty of Biochemical and Pharmaceutical Sciences, National University of Rosario, Suipacha 570, Rosario 2000, Argentina.
Carnovale
C E
CE
Monti
J A
JA
Carrillo
M C
MC
D000818:Animals; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects*; D015536:Down-Regulation; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D009955:Ornithine Decarboxylase / Q000187:drug effects / Q000378:metabolism*; D011073:Polyamines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011073:Polyamines; D011994:Recombinant Proteins; D014316:Tritium; D004247:DNA; D009955:Ornithine Decarboxylase; D013936:Thymidine