MODIFICATIONS OF HEPATIC ALPHA-1-ACID GLYCOPROTEIN AND ALBUMIN GENE-EXPRESSION IN RATS TREATED WITH PHENOBARBITAL

The serum level of alpha-1-acid glycoprotein (alpha-1-AGP) is significantly increased in various animal species by treatment with cytokines, glucocorticoids and phenobarbital. The mechanisms responsible for the cytokine-induced and glucocorticoid-induced increases are now well documented, but not so in the case of phenobarbital. The main purpose of this study was to assess whether phenobarbital acts on alpha-1-AGP synthesis in the liver at the transcriptional or translational level. Male Dark Agouti rats received 70 mg phenobarbital/kg daily for 7 days. The analysis of total hepatic RNA showed that a single injection of phenobarbital induced an 11-fold increase in phenobarbital-dependent cytochrome P450IIB mRNA, whereas seven injections of phenobarbital were required to induce a maximum 5.5-fold increase in alpha-1-AGP mRNA. Concurrently, the transcription rate of the alpha-1-AGP gene rose 3.5-fold. Hepatocytes isolated after the seventh injection of phenobarbital showed a threefold increased capacity to secrete alpha-1-AGP, corresponding to a 3.2-fold increased alpha-1-AGP mRNA content in the liver. In conditions in which its effect on the induction of alpha-1-AGP synthesis was maximum, phenobarbital caused a 30% reduction in liver albumin mRNA and in albumin secretion by isolated hepatocytes, resulting from a 60-70% reduction in the rate of transcription of the albumin gene measured in isolated nuclei. We conclude that the effect of phenobarbital on alpha-1-AGP and albumin gene expression occurs at the transcriptional rather than the translational level.