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.
Bertaux
O
O
Département de Biochimie Générale, Université Paris-Sud, France.
Fournier
T
T
Chauvelot-Moachon
L
L
Porquet
D
D
Valencia
R
R
Durand
G
G
D000418:Albumins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009961:Orosomucoid / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic; D014425:Turpentine / Q000494:pharmacology
D000418:Albumins; D009961:Orosomucoid; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D014425:Turpentine; D010634:Phenobarbital