AhR and PPARalpha: antagonistic effects on CYP2B and CYP3A, and additive inhibitory effects on CYP2C11.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a spectrum of toxic and biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. The peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor super-family of ligand-activated transcription factors and it functions as an obligate heterodimer with retinoid X-receptor alpha RXRalpha. The aim was to investigate whether the negative cross-talk recently proposed by the present authors between AhR and PPARalpha on CYP4A and CYP1A has any impact on other cytochrome P450 enzymes. Treatment of male Wistar rats with a PPARalpha ligand clofibric acid (CA) induced CYP2B1/2 and CYP3A proteins, activities, and the mRNA expression of CYP2B1, CYP2B2, CYP3A1 and CYP3A2, and suppressed CYP2C11 protein, activities and mRNA expression. AhR ligand Sudan III (S.III) treatment decreased basal and CA-induced CYP2B, CYP3A and CYP2C11 protein, activities and mRNA expression. To the best of the authors' knowledge, this is the first study showing the presence of mutual effects of AhR and PPARalpha on CYP2B and CYP3A and an additive inhibitory effect on CYP2C11 in the livers of male rats.
Shaban
Z
Z
Laboratory of Toxicology, Department of Environmental Veterinary Sciences Graduate, School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Soliman
M
M
El-Shazly
S
S
El-Bohi
K
K
Abdelazeez
A
A
Kehelo
K
K
Kim
H-S
HS
Muzandu
K
K
Ishizuka
M
M
Kazusaka
A
A
Fujita
S
S
D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001391:Azo Compounds / Q000008:administration & dosage; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000494:pharmacology; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism*
D001391:Azo Compounds; D004791:Enzyme Inhibitors; D047493:PPAR alpha; D018336:Receptors, Aryl Hydrocarbon; D002995:Clofibric Acid; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C025619:steroid 16-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; C033006:sudan III