ToxSci Advance Access first published online on July 22, 2008
This version published online on August 21, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn147
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Perfluorocarboxylic acids induce cytochrome p450 enzymes in mouse liver through activation of PPAR
and CAR transcription factors
Department of Pharmacology, Toxicology and Therapeutics University of Kansas Medical Center 3901 Rainbow Boulevard Kansas City, KS 66160
* Corresponding author: Curtis D. Klaassen, PhD Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard. Kansas City, KS 66160 Phone: 913-588-7714 Fax: 913-588-7501 E-mail: cklaasse{at}kumc.edu E-mail for each author: Xingguo Cheng, scheng{at}kumc.edu; Curtis D. Klaassen, cklaasse{at}kumc.edu.
Received May 8, 2008; revision received July 15, 2008; accepted July 16, 2008
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Abstract |
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Cytochrome p450 enzymes (Cyps) are major phase-I xenobiotic-metabolizing enzymes. Cyps are regulated by many environmental chemicals and drugs. However, knowledge about regulation of Cyps by perfluorocarboxylic acids, which are persistent in the environment, is limited. Two days after a single intraperitoneal administration (50 mg/kg) of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) increased mRNA expression of Cyp2B10 (20-fold), 3A11 (2-fold), and 4A14 (32-fold), but not Cyp1A1/2 in mouse livers. PFDA and PFOA also markedly increased protein expression of Cyp2B (50-fold) and 4A (10-fold). PFDA increased Cyp4A14 mRNA expression at relatively low doses (0.5 mg/kg), but increased Cyp2B10 mRNA expression only at high doses (>20mg/kg). By using CAR-, PXR-, PPAR
-, and FXR-null mouse models, PPAR and CAR were shown to play central roles in the induction of Cyps by PFDA. Specifically, PFDA increased Cyp4A14 mRNA expression in wild-type mice, but much less in PPAR-null mice. PFDA increased Cyp2B10 mRNA expression in wild-type mice, but not in CAR-null mice. In addition, PFDA increased mRNA expression and nuclear translocation of the transcription factor CAR. Therefore, the current studies provide important insight into understanding the regulatory mechanisms initiated by perfluorocarboxylic acids, and may help to better predict and understand the toxicokinetics and toxicodynamics of various perfluorocarboxylic acids. In conclusion, perfluorocarboxylic acids increased Cyp2B10 and 4A14 expression by activating PPAR and CAR nuclear receptors, respectively. PPAR is activated at much lower doses of PFDA than CAR.
Key Words: Constitutive androstane receptor (CAR); cytochrome p450 enzymes (Cyps); perfluorocarboxylic acids (PFCAs); perfluorodecanoic acid (PFDA); perfluorooctanoic acid (PFOA); peroxisome proliferator-activated receptor alpha (PPAR).
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