PPARalpha-dependent modulation of hepatic CYP1A by clofibric acid in rats.
Fibrates, hypolipidemic drugs, have been reported to suppress the metabolic activities of cytochrome P450 1A1 and 1A2 in rats but the mechanism has not been elucidated. In the present study we tested the hypothesis that the inhibitory effect of fibrates on arylhydrocarbon receptor (AhR) function may be due to their stimulatory effects on PPARalpha. Sudan III (S.III) treatment induced CYP 1A1 and CYP 1A2 protein expression, mRNA and their metabolic activities, methoxyresorufin-O-demethylase (MROD) and ethoxyresorufin-O-deethylase (EROD), in Wistar rats higher than those in the control. Co-treatment of rats with S.III and clofibric acid (CA) caused a 40-50% decrease in the induced levels of CYP1A1 and CYP1A2 protein, mRNA expression and their metabolic activities and reduced AhR protein expression. When we treated HepG2 cells with S.III and/or CA, no suppressive effect on S.III-induced CYP1A1 protein expression due to CA was found. HepG2 cells were transiently transfected with increasing concentrations of PPARalpha mammalian expression vector and exposed to the same treatment. CA co-treatment with S.III decreased AhR protein and S.III-induced CYP1A1 protein expression with increasing dose of PPARalpha transfected into HepG2 cells. Our results demonstrate that the suppressive effect of fibrates on CYP1A is PPARalpha-dependent and suggest that PPARalpha has an inhibitory effect on AhR function.
Shaban
Zein
Z
Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, N18, W9, Kita-ku, 060-0818 Sapporo, Japan.
El-Shazly
Samir
S
Ishizuka
Mayumi
M
Kimura
Kazuhiro
K
Kazusaka
Akio
A
Fujita
Shoichi
S
D000284:Administration, Oral; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001391:Azo Compounds / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002995:Clofibric Acid / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis; D014162:Transfection
C497396:ARNT protein, human; C497398:ARNT protein, rat; D001391:Azo Compounds; D004268:DNA-Binding Proteins; D047493:PPAR alpha; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002995:Clofibric Acid; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C033006:sudan III