Regulation of the Ah gene battery via Ah receptor-dependent and independent processes in cultured adult rat hepatocytes.
A number of genes under the control of the arylhydrocarbon (Ah) receptor were tested for the effects of glucocorticoids on their expression in cultured primary rat hepatocytes. Treatment of cultured hepatocytes with 1.0 microM dexamethasone potentiated the induction (2- to 3-fold) of cytochrome P4501A1, glutathione S-transferase Ya subunit (GSTYa), and UDP-glucuronosyltransferase gene expression by polycyclic aromatic hydrocarbons (PAH), whereas the glucocorticoid agonist suppressed PAH induction of NAD(P)H:quinone oxidoreductase (QOR) subunit and aldehyde dehydrogenase 3C gene expression by 60-80%. These results were seen at the level of enzyme activity for induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin and at the level of enzyme activity, protein, and specific mRNA for induction by 1,2-benzanthracene. Two of these rat genes, GSTYa and QOR are also induced by electrophilic agents, such as t-butylhydroquinone. In the presence of t-butylhydroquinone, dexamethasone caused a similar level of potentiation of GSTYa subunit expression and suppression of QOR subunit expression as was seen with the PAH, 1,2-benzanthracene. Studies using the glucocorticoid receptor antagonist, RU38486, demonstrated that the modulation of PAH induction by glucocorticoids of cytochrome P4501A1 and QOR activity is apparently dependent on action of the glucocorticoid receptor. These results suggest that the positive and negative changes observed are the result of specific alterations in the rates of transcription of these genes because of the action of the glucocorticoid receptor, thereby affecting regulation of GSTYa and QOR by both Ah receptor-dependent and independent mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Xiao
G H
GH
Department of Biochemistry, School of Medicine, University of Louisville, KY 40292, USA.
Pinaire
J A
JA
Rodrigues
A D
AD
Prough
R A
RA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D014453:Glucuronosyltransferase / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006873:Hydroquinones / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D010766:Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D000975:Antioxidants; D006873:Hydroquinones; D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; C018855:2-tert-butylhydroquinone; D016660:NAD(P)H Dehydrogenase (Quinone); D014453:Glucuronosyltransferase; D005982:Glutathione Transferase