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 regenera tion. It has been postulated that interferon-alpha (IFN alpha) decreases pu trescine 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 IFN alpha on po lyamine and ODC levels during the regenerative process following partial he patectomy in rats. Synthesis of ODC by isolated hepatocytes from IFN-treate d rats with regenerating livers was also assessed. Furthermore, we investig ated the effect of IFN alpha -2b on DNA and total protein synthesis in 24-h r regenerating livers. No effect on DNA synthesis was observed at the dose of IFNa-2b used, but total protein synthesis decreased significantly in IFN alpha -2b-treated rats undergoing liver regeneration (7.0 +/- 2.0 and 12.1 +/- 1.7%.min(-1) in hepatectomized rats treated with IFN alpha -2b and sal ine, respectively). ODC levels were also reduced significantly (by 50%) in hepatectomized rats treated with IFN alpha -2b versus saline. In parallel w ith 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 mu mol/ g liver, respectively, in IFN alpha -2b- and saline-treated hepatectomized rats) showed similar, significant diminutions. Moreover, the incorporation of [S-35]methionine into ODC was decreased dramatically in isolated hepatoc ytes from IFN alpha -2b-treated hepatectomized rats 12 hr after surgery. In conclusion, the protein synthesis rate in regenerating liver was impaired by therapeutic doses of IFN alpha -2b. In addition, the results presented i n this study suggest that IFN alpha -2b negatively regulates ODC synthesis, causing a reduction in polyamine levels during liver regeneration. (C) 200 1 Elsevier Science Inc. All rights reserved.