PPARalpha activators down-regulate CYP2C7, a retinoic acid and testosterone hydroxylase.
Peroxisome proliferators (PP) are a large class of structurally diverse chemicals that mediate their effects in the liver mainly through the peroxisome proliferator-activated receptor alpha (PPARalpha). Exposure to PP results in down-regulation of CYP2C family members under control of growth hormone and sex steroids including CYP2C11 and CYP2C12. We hypothesized that PP exposure would also lead to similar changes in CYP2C7, a retinoic acid and testosterone hydroxylase. CYP2C7 gene expression was dramatically down-regulated in the livers of rats treated for 13 weeks by WY-14,643 (WY; 500 ppm) or gemfibrozil (GEM; 8000 ppm). In the same tissues, exposure to WY and GEM and to a lesser extent di-n-butyl phthalate (20,000 ppm) led to decreases in CYP2C7 protein levels in both male and female rats. An examination of the time and dose dependence of CYP2C7 protein changes after PP exposure revealed that CYP2C7 was more sensitive to compound exposure compared to other CYP2C family members. Protein expression was decreased after 1, 5 and 13 weeks of PP treatment. CYP2C7 protein expression was completely abolished at 5 ppm WY, the lowest dose tested. GEM and DBP exhibited dose-dependent decreases in CYP2C7 protein expression, becoming significant at 1000 ppm or 5000 ppm and above, respectively. These results show that PP exposure leads to changes in CYP2C7 mRNA and protein levels. Thus, in addition to known effects on steroid metabolism, exposure to PP may alter retinoic acid metabolism.
Fan
Li-Qun
LQ
CIIT Centers for Health Research, Six Davis Drive, PO Box 12137, Research Triangle Park, NC 27709-2137, USA.
Brown-Borg
Holly
H
Brown
Sherri
S
Westin
Stefan
S
Mode
Agneta
A
Corton
J Christopher
JC
D000818:Animals; D019138:Antibodies, Blocking / Q000737:chemistry; D001711:Biotransformation / Q000502:physiology; D015152:Blotting, Northern; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D003993:Dibutyl Phthalate / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015248:Gemfibrozil / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D047492:Peroxisome Proliferator-Activated Receptors / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics
D019138:Antibodies, Blocking; D047492:Peroxisome Proliferator-Activated Receptors; D011743:Pyrimidines; D003993:Dibutyl Phthalate; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; C493085:Cyp2c7 protein, rat; D000072467:Cytochrome P450 Family 2; D015248:Gemfibrozil