3-Methylcholanthrene and Phenobarbital Stimulation of Rat Liver RNA Polymerase

Abstract

3-METHYLCHOLANTHRENE and phenobarbital represent two classes of drugs which markedly increase the activity of a variety of rat liver microsomal enzyme systems¹. Both these agents increase microsomal amino-acid incorporation^2,3. Phenobarbital increases the sensitivity of microsomes to polyuridylic acid directed phenylalanine incorporation³ and causes a proliferation of the agranular endoplasmic reticulum^4,5. The stimulation by 3-methyl-cholanthrene of two of the microsomal enzymes, benzpyrene hydroxylase and aminoazo dye demethylase, is prevented by puromycin^6,7 and by actinomycin D (ref. 6), suggesting that the effects of 3-methylcholanthrene are dependent on protein synthesis mediated by DNA-directed RNA synthesis. In other investigations 3-methylcholanthrene was reported to stimulate incorporation of orotic acid into nuclear RNA and to increase significantly the net amount of rat liver nuclear RNA⁸. This work reports that 3-methylcholanthrene and phenobarbital stimulate rat liver DNA-dependent RNA polymerase activity. DNA isolated from the livers of the drug-treated rats and control rats, however, shows identical template activity when measured with purified RNA polymerase from M. lysodeikticus. The increased RNA polymerase activity in the liver nuclei of rats treated with 3-methylcholanthrene and phenobarbital demonstrates the stimulatory effect of these agents on gene activity and supports the hypothesis that the stimulation of microsomal enzyme synthesis by the two drugs is mediated through an activation of DNA-dependent RNA synthesis.