Posttranscriptional regulation of coumarin 7-hydroxylase induction by xenobiotics in mouse liver: mRNA stabilization by pyrazole.
The induction mechanism by pyrazole or phenobarbital of coumarin 7-hydroxylase (cytochrome P450coh) was investigated in DBA/2J male mice. The P450coh mRNA in the pyrazole-induced mice was increased gradually to a 20-fold higher level within 48 h, yet transcription of the P450coh gene was not affected. The half-life of P450coh mRNA, on the other hand, was at least 4-fold longer in the pyrazole-induced DBA/2J (approximately 6.0 h) than in control DBA/2J (approximately 1.5 h) male mice. The stabilization of P450coh mRNA, therefore, is the primary mechanism for the induction by pyrazole of coumarin 7-hydroxylase. Phenobarbital, on the other hand, regulates the induction either translationally or posttranslationally. This drug affected neither the P450coh mRNA nor the P450coh gene's transcription levels in the DBA/2J male mice, although Western blots showed approximately a 3-fold increase of the P450coh protein in the liver microsomes of the drug-treated mice. The results indicate, therefore, that both phenobarbital and pyrazole regulate the P450coh induction posttranscriptionally; the former inducer enhances the translational efficiency of P450coh mRNA or alters the degradation rate of P450coh aproprotein, while the latter stabilizes P450coh mRNA.
Aida
K
K
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709.
Negishi
M
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics*; D010634:Phenobarbital / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D015262:Xenobiotics / Q000494:pharmacology*
D011720:Pyrazoles; D012333:RNA, Messenger; D015262:Xenobiotics; C031280:pyrazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D010634:Phenobarbital