Faculty Collaboration Database

The induction of hepatic cytochrome P450 3A in rats: effects of age. Proc Soc Exp Biol Med 1995 Nov;210(2):134-9

Date

11/01/1995

Pubmed ID

7568283

DOI

10.3181/00379727-210-43932

Scopus ID

2-s2.0-0028841524 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

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.

Author List

Lee PC, Werlin SL

Author

Steven L. Werlin MD Emeritus Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aging
Animals
Cycloheximide
Cytochrome P-450 CYP2E1
Cytochrome P-450 Enzyme System
DNA Probes
Dactinomycin
Dexamethasone
Dose-Response Relationship, Drug
Enzyme Induction
Female
Kinetics
Liver
Male
Microsomes, Liver
Mixed Function Oxygenases
Pregnancy
Protein Synthesis Inhibitors
RNA, Messenger
Rats
Rats, Sprague-Dawley
Time Factors