Developmental aspects of glucocorticoid regulation of polycyclic aromatic hydrocarbon-inducible enzymes in rat liver.
The expression of hepatic cytochrome P4501A1 (P4501A1), glutathione S-transferase Ya subunit (GST), and NAD(P)H:quinone oxidoreductase (QOR) proteins was evaluated in fetal, neonatal, and adolescent rats treated with 3-methylcholanthrene (MC) and the synthetic glucocorticoid dexamethasone (Dex) to elucidate the developmental aspects of glucocorticoid regulation of the induction of drug metabolizing enzymes by polycyclic aromatic hydrocarbons in vivo. These developmental states were chosen to represent either glucocorticoid deplete or replete conditions due to their differences in circulating glucocorticoid levels. Rats were treated with either MC (10 mg/kg body wt) or Dex (10 mg/kg body wt) or a combination of both and sacrificed 24 h later. In neonatal rats, the enzyme activities of P4501A1, GST, and QOR were increased by MC treatment approximately 65-, 1.4-, and 7-fold, respectively. The induction of these enzymes by MC was further potentiated an additional 2-, 1.5-, and 1.4-fold by concomitant Dex treatment. In adolescent male rats, Dex potentiated MC induction of P4501A1 activity (1.7-fold), but repressed MC induction of GST and QOR activities. When the protein contents for the three enzymes were measured by Western blot analyses, a positive correlation was observed with enzyme activities for all conditions except for the adolescent rat, where hepatic protein content of P4501A1 of rats treated with both MC and Dex was not significantly increased above the level seen with 3-methylcholanthrene treatment alone. The levels of specific mRNA and transcriptional activity for cytochrome P4501A1, GST Ya isozyme, and QOR closely paralleled the changes seen in their protein content in the livers of neonatal and adolescent rats. Dexamethasone potentiation of P4501A1 expression at the protein and RNA level were clearly statistically significant in the neonatal rat, but not in the adolescent rat, suggesting that the circulating levels of glucocorticoids are sufficiently low during the neonatal period that the full expression of induction of P4501A1 was not attained in the absence of exogenously administered glucocorticoids. These data also demonstrate that glucocorticoids have differential effects on the induction of GST Ya subunit and QOR protein and RNA in the neonatal and adolescent state, possibly related to circulating levels of glucocorticoids.
Linder
M W
MW
Department of Biochemistry, School of Medicine, University of Louisville, Kentucky 40292.
Prough
R A
RA
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000096:biosynthesis; D008099:Liver / Q000196:embryology / Q000201:enzymology* / Q000254:growth & development*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008954:Models, Biological; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D011083:Polycyclic Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005938:Glucocorticoids; D011083:Polycyclic Compounds; D008748:Methylcholanthrene; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase