Dexamethasone negatively regulates phenobarbitone-activated transcription but synergistically enhances cytoplasmic levels of cytochrome P-450b/e messenger RNA.
Dexamethasone has a potentiating effect on phenobarbitone mediated induction of cytochrome P-450b + e mRNAs in adult rat liver. However, the glucocorticoid inhibits phenobarbitone-activated transcription of cytochrome P-450b + e mRNAs by 60-70%. This inhibitory effect is evident in run-off transcription of the endogenous genes as well as in the transcription of an added cloned gene fragment. Dexamethasone inhibits the phenobarbitone-mediated increase in the binding of a transcription factor(s) to the upstream region of the gene as evidenced by gel retardation and Southwestern blot analysis. The glucocorticoid does not stabilize the phenobarbitone-induced polyribosomal cytochrome P-450b + e mRNAs but appears to stabilize the nuclear transcripts. It is proposed that a negative element may mediate the action of dexamethasone at the level of nuclear transcription and stabilization of the nuclear transcript may account for the potentiating effect of the glucocorticoid on phenobarbitone-mediated increase in cytochrome P-450b + e mRNAs in the cytoplasm of the adult rat liver. However, the cytochrome P-450b protein levels are slightly lower in phenobarbitone + dexamethasone treatment than in phenobarbitone-treated liver microsomes.
Rao
M V
MV
Department of Biochemistry and Centre for Genetic Engineering, Indian Institute of Science, Bangalore.
Rangarajan
P N
PN
Padmanaban
G
G
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D015245:Deoxyribonuclease BamHI; D015252:Deoxyribonucleases, Type II Site-Specific; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D009693:Nucleic Acid Hybridization; D015345:Oligonucleotide Probes; D010634:Phenobarbital / Q000494:pharmacology*; D011132:Polyribosomes / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D014157:Transcription Factors; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D015245:Deoxyribonuclease BamHI; C052380:endodeoxyribonuclease NcoI; D015252:Deoxyribonucleases, Type II Site-Specific; D010634:Phenobarbital