Regulation of cytochrome P-450 gene expression. Studies with a cloned probe.
A cDNA clone for cytochrome P-450e, a phenobarbitone-inducible species in rat liver, has been isolated and characterized. With the use of this cloned DNA, an attempt has been initiated to elucidate the factors regulating the cytochrome P-450 gene expression. Inhibitors of heme synthesis such as cobalt chloride and 3-amino-1,2,4-triazole block the induction of cytochrome P-450e by phenobarbitone at the level of transcription. This is evident from the decrease in the rate of synthesis of cytochrome P-450e, a decrease in the levels of specific translatable messenger RNA, a decrease in the specific cytoplasmic and nuclear messenger RNA contents, and nuclear transcription of cytochrome P-450e gene, as revealed by hybridization to the cloned probe, under these conditions. It is proposed that heme is a general regulator of cytochrome P-450 gene expression at the level of transcription, whereas the drug or its metabolite would impart the specificity needed for the induction of a particular species.
D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D003035:Cobalt / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA; D005786:Gene Expression Regulation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D010634:Phenobarbital / Q000494:pharmacology; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D012333:RNA, Messenger; D003035:Cobalt; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C018021:cobaltous chloride; D010634:Phenobarbital; D000640:Amitrole