Modulation of P-450 IIC7 and IIIA1,2 mRNA in pre-neoplastic liver. Effect of promotion by phenobarbital

Abstract

P-450 IIC7 and IIIA2 mRNAs are constitutively expressed in the hepatic tissue under developmental control. Both forms — as well as IIIA1, 90% homologous to IIIA2 mRNA — display positive modulation by phenobarbital a prototype inducer of the liver monooxygenases and a strong promoter of experimental chemical hepatocarcinogenesis. In the present work the variations in the concentration of these P-450 mRNA were studied in rats submitted to the hepatocarcinogenic protocol of Solt and Farber. We demonstrate that a decrease in the relative concentrations of P-450 IIC7 and IIIA1,2 mRNA is set up along the tumor promotion stage. Animals — starting the experimental carcinogenic protocol at pubertal age — show a partial inhibition of the physiological expression of P-450 IIIA1,2 mRNA associated to male sex maturation. Administration of phenobarbital results in an acceleration of the pre-neoplastic process which is concomitant with an induction of P-450 IIC7 as well as IIIA1,2 at the earlier promotion stages. P-450 mRNA concentration markedly decreases as the preneoplastic process develops. While an impaired P-450 IIIA1,2 mRNA relative abundance is observed, an inversion of the modulation of P-450 IIC7 as well as of the male phenotype marker α-2u-globulin mRNA arises as the tumor promotion stage progresses, both mRNA becoming repressed in response to phenobarbital.