Induction of the hepatic mixed-function oxidase system by synthetic glucocorticoids. Transcriptional and post-transcriptional regulation.
Quantitative evaluation of transcriptional rates in isolated nuclei and intranuclear and cytoplasmic mRNA levels demonstrates that the catatoxic steroids pregnenolone-16 alpha-carbonitrile (PCN) and dexamethasone modulate microsomal drug metabolizing enzymes both positively and negatively at the transcriptional level. Additionally, a strong post-transcriptional influence, believed to be message stabilization, was found to be exerted by dexamethasone. Both NADPH-cytochrome P-450b-homologous mRNA are induced 7- and 12-fold, respectively, presumably through message stabilization. Under these conditions, however, the oxidoreductase content of the cell is only marginally increased while the cytochrome P-450b level is actually decreased by 40% within three days after a single injection of dexamethasone. In contrast, genes coding for cytochromes P-450PCN show a definite increase in transcription following administration of either pre gnenolone-16 alpha-carbonitrile or dexamethasone, whereas transcription of the epoxide hydrolase gene is markedly reduced by administration of these compounds.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000235:genetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000235:genetics; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
D012333:RNA, Messenger; D012709:Serum Albumin; D011285:Pregnenolone Carbonitrile; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase; D004851:Epoxide Hydrolases