Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes.
CYP1A1 and CYP1A2 genes encode members of the cytochrome P450 superfamily of enzymes primarily involved in xenobiotic and drug metabolism. In this paper we examined the effects of synthetic glucocorticoid dexamethasone (DEX) on aryl hydrocarbon receptor (AhR)-mediated regulation of CYP1A1 and CYP1A2 genes and their enzymatic activity in primary cultures of human hepatocytes obtained from 17 donors and prepared in 3 countries. Dexamethasone significantly reduced both basal and inducible CYP1A1/2 ethoxyresorufin-O-deethylase (EROD) activities by more than 75 and 50%, respectively. Glucocorticoid receptor (GR) antagonist RU486 abolished this effect suggesting the involvement of GR in the process. In contrast, dexamethasone significantly augmented transcriptional activation of CYP1A2 mRNA but not CYP1A1 gene by prototype AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3MC). Dexamethasone had no effect on basal and TCDD-inducible levels of CYP1As proteins; however, it reduced the levels of AhR and GRalpha mRNAs and AhR protein levels. In addition, using RT(2) Profiler PCR Array, we found the effect of dexamethasone on the expression of several co-activators of AhR and GR nuclear receptors in the primary human hepatocytes. We conclude that dexamethasone controls CYP1A1 and CYP1A2 expression and activity in human hepatocytes via multiple mechanisms, which remain to be elucidated.
Vrzal
Radim
R
Department of Cell Biology and Genetic, Faculty of Science, Palacky University, Slechtitelu 11, 783 71 Olomouc, Czech Republic.
Stejskalova
Lucie
L
Monostory
Katalin
K
Maurel
Patrick
P
Bachleda
Petr
P
Pavek
Petr
P
Dvorak
Zdenek
Z
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D018153:Czech Republic; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005602:France; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D006814:Hungary; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity; D008875:Middle Aged; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D008748:Methylcholanthrene; D003907:Dexamethasone; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2