RIBAVIRIN INHIBITS PROTEIN-SYNTHESIS AND CELL-PROLIFERATION INDUCED BY MITOGENIC FACTORS IN PRIMARY HUMAN AND RAT HEPATOCYTES

Ribavirin, a guanosine analog, used in combination with interferon alp ha (IFN-alpha) in the treatment of chronic hepatitis induced by hepati tis C virus (HCV) infection, has been shown to improve liver histology and to decrease transaminases even when administered alone. We analyz ed the direct effects of ribavirin on the liver by using primary cultu res of human and rat hepatocytes. Between 10 to 60 mu mol/L, ribavirin was found to inhibit both the synthesis and secretion of whole protei ns in a time- and dose-dependent fashion. Such an effect was confirmed by the measurement of albumin and haptoglobin secretion rates. [H-3]- Thymidine incorporation was suppressed both in hepatocyte growth facto r-stimulated human hepatocytes and in epidermal growth factor (EGF)-st imulated rat hepatocytes in the presence of ribavirin, The inhibitory effect on DNA synthesis was associated with a delayed progression to S phase of the cell cycle, as determined by flow cytometry and detectio n of cyclin A and cdc2 which are two proteins expressed during the S p hase. The inhibition of DNA synthesis, caused by 50 mu mol/L ribavirin , was completely restored by the addition of 80 mu mol/L guanosine. Th ese observations demonstrate that ribavirin at concentrations close to those found in plasma of treated patients can directly affect hepatic functions in vitro. Its effects could, however, be reduced in vivo by guanosine salvage supply.