Clofibrate and perfluorodecanoate both upregulate the expression of the pregnane X receptor but oppositely affect its ligand-dependent induction on cytochrome P450 3A23.
The pregnane X receptor (PXR) interacts with a vast array of structurally dissimilar chemicals and confers induction of several major types of drug metabolizing enzymes such as cytochrome P450s (CYP). We previously reported that the expression of PXR was markedly increased in rats treated with clofibrate and perfluorodecanoic acid (PFDA). The present study was undertaken to test the hypothesis that induced expression of PXR increases PXR ligand-dependent induction on CYP3A23. Rat hepatocytes were treated with clofibrate or PFDA individually, or along with PXR ligand pregnenolone 16alpha-carbonitrile (PCN), and the levels of PXR and CYP3A23 were determined by Western blots. Both clofibrate and PFDA markedly increased the expression of PXR with PFDA being more potent, and the induction was abolished by actinomycin D, an inhibitor for mRNA synthesis. As expected, PCN alone markedly induced the expression of CYP3A23. Interestingly, co-treatment with clofibrate enhanced the induction, whereas co-treatment with PFDA suppressed it. Clofibrate and PFDA represent multi-classes of chemicals called peroxisome proliferators including many therapeutic agents and industrial pollutants. The opposing effects of clofibrate and PFDA on the PCN-induced expression of CYP3A23 suggest that peroxisome proliferators likely increase the expression of PXR but differentially alter its ligand-dependent induction. The interaction between PXR inducer and ligand provides a novel mechanism on how functionally and structurally distinct chemicals cooperatively regulate the expression of xenobiotic-metabolizing enzymes and transporters.
Ma
Yuzhong
Y
Department of Biomedical Sciences, University of Rhode Island, 41 Lower College Road, Kingston, RI 02881, USA.
Sachdeva
Karuna
K
Liu
Jirong
J
Song
Xiulong
X
Li
Yuxin
Y
Yang
Dongfang
D
Deng
Ruitang
R
Chichester
Clinton O
CO
Yan
Bingfang
B
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003609:Dactinomycin / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology*; D005466:Fluorocarbons / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008297:Male; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D011987:Receptors, Steroid / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000187:drug effects*
D003652:Decanoic Acids; D005466:Fluorocarbons; D008024:Ligands; D000077297:Pregnane X Receptor; D011506:Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011285:Pregnenolone Carbonitrile; D003609:Dactinomycin; C036567:perfluorodecanoic acid; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D002994:Clofibrate