Perfluorocarboxylic acids induce cytochrome p450 enzymes in mouse liver through activation of PPAR-α and CAR transcription factors

被引:74
作者
Cheng, Xingguo [1 ]
Klaassen, Curtis D. [1 ]
机构
[1] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA
基金
美国国家卫生研究院;
关键词
constitutive androstane receptor (CAR); cytochrome p450 enzymes (Cyps); perfluorocarboxylic acids (PFCAs); perfluorodecanoic acid (PFDA); perfluorooctanoic acid (PFOA); peroxisome proliferator-activated receptor alpha (PPAR-alpha);
D O I
10.1093/toxsci/kfn147
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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 (PFCAs), which are persistent in the environment, is limited. Two days after a single i.p. administration (50 mg/kg) of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) increased mRNA expression of Cyp2B10 (20-fold), 3A11 (two-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 (> 20 mg/kg). By using constitutive androstane receptor (CAR)-, pregnane-X receptor (PXR)-, peroxisome proliferator-activated receptor alpha (PPAR)-alpha-, and farnesoid X receptor-null mouse models, PPAR-alpha and CAR were shown to play central roles in the induction of Cyps by PFDA. Specifically, PFDA increased Cyp4A14 mRNA expression in wild-type (WT) mice, but much less in PPAR-alpha-null mice. PFDA increased Cyp2B10 mRNA expression in WT 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 PFCAs, and may help to better predict and understand the toxicokinetics and toxicodynamics of various PFCAs. In conclusion, PFCAs increased Cyp2B10 and 4A14 expression by activating PPAR-alpha and CAR nuclear receptors, respectively. PPAR-alpha is activated at much lower doses of PFDA than CAR.
引用
收藏
页码:29 / 36
页数:8
相关论文
共 40 条
[1]   Effects of peroxisome proliferators on rat liver phospholipids: Sphingomyelin degradation may be involved in hepatotoxic mechanism of perfluorodecanoic acid [J].
Adinehzadeh, M ;
Reo, NV .
CHEMICAL RESEARCH IN TOXICOLOGY, 1998, 11 (05) :428-440
[2]   Peroxisome proliferator-activated receptor-α regulates lipid homeostasis, but is not associated with obesity -: Studies with congenic mouse lines [J].
Akiyama, TE ;
Nicol, CJ ;
Fievet, C ;
Staels, B ;
Ward, JM ;
Auwerx, J ;
Lee, SST ;
Gonzalez, FJ ;
Peters, JM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (42) :39088-39093
[3]   THE BIOCHEMICAL TOXICITY OF PERFLUORODECANOIC ACID IN THE MOUSE IS DIFFERENT FROM THAT OF 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN [J].
BREWSTER, DW ;
BIRNBAUM, LS .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1989, 99 (03) :544-554
[4]   HEPATIC OXIDATIVE STRESS AND RELATED DEFENSES DURING TREATMENT OF MICE WITH ACETYLSALICYLIC-ACID AND OTHER PEROXISOME PROLIFERATORS [J].
CAI, YN ;
APPELKVIST, EL ;
DEPIERRE, JW .
JOURNAL OF BIOCHEMICAL TOXICOLOGY, 1995, 10 (02) :87-94
[5]   Perfluorochemicals in pooled serum samples from United States residents in 2001 and 2002 [J].
Calafat, AM ;
Kuklenyik, Z ;
Caudill, SP ;
Reidy, JA ;
Needham, LL .
ENVIRONMENTAL SCIENCE & TECHNOLOGY, 2006, 40 (07) :2128-2134
[6]   Nuclear receptor, pregnane X receptor, is required for induction of UDP-glucuronosyltransferases in mouse liver by pregnenolone-16α-carbonitrile [J].
Chen, C ;
Staudinger, JL ;
Klaassen, CD .
DRUG METABOLISM AND DISPOSITION, 2003, 31 (07) :908-915
[7]   Tissue distribution and ontogeny of mouse organic anion transporting polypeptides (Oatps) [J].
Cheng, XG ;
Maher, J ;
Chen, C ;
Klaassen, CD .
DRUG METABOLISM AND DISPOSITION, 2005, 33 (07) :1062-1073
[8]   Regulation of mRNA expression of xenobiotic transporters by the pregnane X receptor in mouse liver, kidney, and intestine [J].
Cheng, Xingguo ;
Klaassen, Curtis D. .
DRUG METABOLISM AND DISPOSITION, 2006, 34 (11) :1863-1867
[9]   INDUCTION OF THE CYP4A SUBFAMILY BY PERFLUORODECANOIC ACID - THE RAT AND THE GUINEA-PIG AS SUSCEPTIBLE AND NON-SUSCEPTIBLE SPECIES [J].
CHINJE, E ;
KENTISH, P ;
JARNOT, B ;
GEORGE, M ;
GIBSON, G .
TOXICOLOGY LETTERS, 1994, 71 (01) :69-75
[10]   Presence and inducibility of peroxisomes in a human glioblastoma cell line [J].
Cimini, A ;
Cristiano, L ;
Bernardo, A ;
Farioli-Vecchioli, S ;
Stefanini, S ;
Cerù, MP .
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 2000, 1474 (03) :397-409