Dexamethasone transcriptionally increases the expression of the pregnane X receptor and synergistically enhances pyrethroid esfenvalerate in the induction of cytochrome P450 3A23.
The pregnane X receptor (PXR) is recognized as a key regulator for the induction of a large number of genes in drug metabolism and transport. The transactivation of PXR is enhanced by the glucocorticoid dexamethasone and the enhancement is linked to the induction of PXR in humans and rats. The present study was undertaken to determine the mechanism for the induction and ascertain the synergistic effect on the expression of CYP3A23, a rat PXR target. In primary hepatocytes, significant induction of PXR was detected as early as 2h after the treatment and the maximal induction occurred at 1 microM dexamethasone. Similar induction kinetics was observed in the hepatoma line H4-II-E-C3. The induction was abolished by actinomycin D and dexamethasone efficaciously stimulated the rat PXR promoter. In addition, dexamethasone synergized esfenvalerate (an insecticide and a PXR activator) in inducing CYP3A23 and stimulating the CYP3A23 promoter. The full promoter of CYP3A23 (-1445/+74) was activated in a similar pattern as the changes in PXR mRNA in response to dexamethasone, esfenvalerate and co-treatment. In contrast, different responding patterns were detected on the stimulation of the CYP3A23 proximal promoter. Synergistic stimulation was also observed on the CYP3A4-DP-Luc reporter, the human counterpart of CYP3A23. These findings establish that transactivation is responsible for the induction of rat PXR and the induction presents potential interactions with insecticides in a species-conserved manner. The different responding patterns among CYP3A23 reporters point to an involvement of multiple transcriptional events in the regulation of CYP3A23 expression by dexamethasone, esfenvalerate and both.
Shi
Deshi
D
Department of Biomedical Sciences, Center for Pharmacogenomics and Molecular Therapy, University of Rhode Island, 41 Lower College Road, Kingston, RI 02881, USA.
Yang
Dongfang
D
Yan
Bingfang
B
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D011722:Pyrethrins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D009570:Nitriles; D000077297:Pregnane X Receptor; D011722:Pyrethrins; D011987:Receptors, Steroid; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C017690:fenvalerate