The induction of hepatic cytochrome P450 3A in rats: effects of age.
Liver microsomal cytochrome P450 3A (CYP3A) concentrations were evaluated by Western blots using specific antisera. Low levels of CYP3A protein were found in untreated animals. Dexamethasone (DX) treatment resulted in a significant induction of CYP3A. The induction was dose and time dependent. Addition of U486 (a specific type II glucocorticoid receptor antagonist), but not spironolactone (a specific type I receptor antagonist) blocked the induction of CYP3A proteins by dexamethasone, suggesting a receptor-mediated mechanism. Concomitant administration of either actinomycin D or cyclohexamide, together with dexamethasone completely abolished the induction of CYP3A protein by dexamethasone, suggesting the requirement of both protein and RNA synthesis. A comparison of the inducibility of CYP3A protein by dexamethasone in rats from different age groups showed that the degree of increase was higher in the younger than in the older groups (e.g., 5 days versus adult). Thus, there is an attenuation in the responsiveness to dexamethasone induction of CYP3A proteins with age. Evaluation of the steady-state levels of CYP3A mRNA by Northern blots showed increases in mRNA following DX treatment in both young and old rats. The final level of CYP3A mRNA reached after DX treatment was higher in the pups than that found in similarly treated older rats. This decrease in responsiveness in older animals appeared to manifest at least in part of the pretranslational level.
Lee
P C
PC
Department of Pediatrics, Medical College of Wisconsin, Milwaukee 53226, USA.
Werlin
S L
SL
D000375:Aging / Q000378:metabolism; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015342:DNA Probes; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D011247:Pregnancy; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D015342:DNA Probes; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D003609:Dactinomycin; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D003513:Cycloheximide; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1