Toxicology 203 (2004) 41–48 PPAR activators down-regulate CYP2C7, a retinoic acid and testosterone hydroxylase Li-Qun Fan a,1 , Holly Brown-Borg b , Sherri Brown a , Stefan Westin c,2 , Agneta Mode c , J. Christopher Corton d,∗ a CIIT Centers for Health Research, Six Davis Drive, P.O. Box 12137, Research Triangle Park, NC 27709-2137, USA b Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine, 501 N. Columbia Road, Grand Forks, ND 58203-2817, USA c Department of Medical Nutrition, Huddinge University Hospital, Novum S-141 86, Huddinge, Sweden d ToxicoGenomics, 209 Silver Creek Trail, Chapel Hill, NC 27514, USA Received 26 February 2004; received in revised form 20 May 2004; accepted 23 May 2004 Available online 26 June 2004 Abstract 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  (PPAR). 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 5ppm 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. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Retinoic acid hydroxylase; CYP2C7; Testosterone hydroxylase; Peroxisome proliferator; PPAR; Liver Abbreviations: CYP, cytochrome P450; DBP, di-n-butyl phthalate; GEM, gemfibrozil; PBST, phosphate buffered saline-Tween; PP, peroxisome proliferator; PPAR, peroxisome proliferator-activated receptor ; PPRE, PP responsive element; RXR, retinoid X receptor; WY, WY-14,643. ∗ Corresponding author. Tel.: +1 919 801 0887; fax: +1 919 408 0365. E-mail address: ccorton@msn.com (J.C. Corton). 1 Present Address: Corixa Corp, 1124 Columbia Street, Seattle, WA 98104, USA. 2 Present address: X-Ceptor Therapeutics, Inc., 4757 Nexus Center Drive, Suite 200, San Diego, CA 92121, USA. 0300-483X/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.tox.2004.05.013