Potentiation of 3-methylcholanthrene induction of rat hepatic cytochrome P450IA1 by dexamethasone in vivo.
The potentiation of the expression of polycyclic aromatic hydrocarbon-inducible cytochromes P450IA1 and P450IA2, and phenobarbital-inducible cytochrome P450IIB1 and NADPH-cytochrome P-450 reductase by dexamethasone in vivo was investigated using adrenalectomized and sham-operated rats. Hepatic cytochrome P450IA1 activity (determined by ethoxyresorufin O-deethylase activity) was induced maximally (30-fold) in both sham-operated and adrenalectomized rats 24 hr after a single injection of 3-methylcholanthrene (10 mg/kg). Dexamethasone (10 mg/kg) increased hepatic tyrosine aminotransferase activity 3- to 4-fold, but had little or no effect on ethoxyresorufin O-deethylase activity. However, dexamethasone potentiated the 3-methylcholanthrene-dependent induction of hepatic P450IA1 activity 2- to 3-fold in adrenalectomized rats and 1.5- to 2-fold in sham-operated rats when administered concomitantly with 3-methylcholanthrene (P less than .05). The dose of dexamethasone required to potentiate 3-methylcholanthrene induction of P450IA1 activity (greater than 1 mg/kg) correlated well with the dose required to induce hepatic tyrosine aminotransferase activity; a marker of glucocorticoid action. Potentiation of 3-methylcholanthrene induction of P450IA1 activity in the rat appears to be tissue specific in that dexamethasone was found not to potentiate 3-methylcholanthrene induction of P450IA1 activity of rat lung or kidney. Cytochrome P450IA1 content induced by 3-methylcholanthrene in the liver was also potentiated 2- to 3-fold by dexamethasone. In contrast, potentiation of 3-methylcholanthrene induction of cytochrome P450IA2 content was not observed. Western blot analyses indicate that the increase in monooxygenase activity induced by 3-methylcholanthrene or 3-methylcholanthrene plus dexamethasone corresponds well only with the induction of cytochrome P450IA1 protein content.(ABSTRACT TRUNCATED AT 250 WORDS)
Sherratt
A J
AJ
Department of Biochemistry, University of Louisville School of Medicine, Kentucky.
Banet
D E
DE
Linder
M W
MW
Prough
R A
RA
D000315:Adrenalectomy; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000201:enzymology*; D008748:Methylcholanthrene / Q000494:pharmacology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000096:biosynthesis; D011083:Polycyclic Compounds / Q000494:pharmacology; D051381:Rats; D014444:Tyrosine Transaminase / Q000096:biosynthesis
D011083:Polycyclic Compounds; D008748:Methylcholanthrene; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase; D014444:Tyrosine Transaminase