Interferon and its inducers are well known to depress drug biotransformation in the liver by decreasing the levels of cytochrome P-450 in that organ. We now report that IFN-alpha-Con1, which was constructed from the most frequently observed amino acid sequences in human alpha-interferon subtypes, causes a loss in cytochrome P-450 which could be prevented by pretreating animals with either puromycin or actinomycin D. This suggests that the loss in drug biotransformation is mediated via the production of an intermediate protein. When the turnover of microsomal protein was examined this interferon appeared to depress the synthesis of proteins with molecular weights 46-60 kd and had little effect on the synthesis of other proteins. The in vitro translation of proteins of molecular weights 45-60 kd was also depressed in an in vitro translation system using mRNA isolated from the livers of interferon treated hamsters. Interferon had no effect on the degradation of microsomal proteins of all molecular weights. It is concluded that interferon probably depresses the levels of cytochrome P-450 in the liver by decreasing the synthesis of the apoprotein and that interferon has little effect on the degradation of the hemoprotein.