Influence of cyclosporine A on protein synthesis in rat liver.

The influence of the immunosuppressive agent cyclosporine A on protein synthesis was investigated in rat liver in vivo and in vitro. Incorporation of [14C]leucine into total protein by microsomes was inhibited 36% in the presence of cyclosporine A. Treatment of rats with cyclosporine A also resulted in decreased protein synthesis by microsomes isolated from the same animals. This inhibition was dependent on the dose administered and the duration of treatment. The inhibitory factor in this latter case appeared to be associated with the supernatant fraction. Decreased in vivo incorporation of [35S]methionine into proteins of microsomal membranes and peroxisomes, but not into microsomal luminal proteins was also observed after treatment of rats with cyclosporine A. On SDS-polyacrylamide gel electrophoresis certain of the microsomal membrane and peroxisomal proteins displayed decreased labeling. Furthermore, cyclosporine A treatment decreased the inductive effects of phenobarbital, clofibrate, and phthalate ester on microsomal and peroxisomal enzymes. It is suggested that certain of the toxic effects of cyclosporine A are exerted through inhibition of cellular protein synthesis.