The environmental estrogen, nonylphenol, activates the constitutive androstane receptor.
Nonylphenol (NP) and its parent compounds, the nonylphenol ethoxylates are some of the most prevalent chemicals found in U.S. waterways. NP is also resistant to biodegradation and is a known environmental estrogen, which makes NP a chemical of concern. Our data show that NP also activates the constitutive androstane receptor (CAR), an orphan nuclear receptor important in the induction of detoxification enzymes, including the P450s. Transactivation assays demonstrate that NP increases murine CAR (mCAR) transcriptional activity, and NP treatment can overcome the inhibitory effects of the inverse agonist, androstanol, on mCAR activation. Treatment of wild-type (CAR +/+) mice with NP at 50 or 75 mg/kg/day increases Cyp2b protein expression in a dose-dependent manner as demonstrated by Western blotting, and was confirmed by quantitative reverse transcription-PCR of Cyp2b10 transcript levels. CAR-null (CAR -/-) mice show no increased expression of Cyp2b following NP treatment, indicating that CAR is required for NP-mediated Cyp2b induction. In addition, NP increases the translocation of CAR into the nucleus, which is the key step in the commencement of CAR's transcriptional activity. NP also induced CYP2B6 in primary human hepatocytes, and increased Cyp2b10 messenger RNA and protein expression in humanized CAR mice, indicating that NP is an activator of human CAR as well. In conclusion, NP is a CAR activator, and this was demonstrated in vitro with transactivation assays and in vivo with transgenic CAR mouse models.
Hernandez
Juan P
JP
Biological Sciences, The University of Texas at El Paso, El Paso, Texas 79968, USA.
Huang
Wendong
W
Chapman
Laura M
LM
Chua
Steven
S
Moore
David D
DD
Baldwin
William S
WS
D000328:Adult; D000368:Aged; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D000072467:Cytochrome P450 Family 2; D052244:Endocrine Disruptors / Q000633:toxicity; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D010636:Phenols / Q000633:toxicity*; D000077297:Pregnane X Receptor; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D014157:Transcription Factors / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015049:Zoxazolamine / Q000494:pharmacology
D000090702:Constitutive Androstane Receptor; D052244:Endocrine Disruptors; D004967:Estrogens; D009125:Muscle Relaxants, Central; D010636:Phenols; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C025256:nonylphenol; D015049:Zoxazolamine; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C101679:Cyp2b10 protein, mouse; D065702:Cytochrome P-450 CYP2B6; D000072467:Cytochrome P450 Family 2; D010089:Oxidoreductases, N-Demethylating