Cited by 52Effects and risks of endocrine disrupting chemicalsPharmacogenetics and Drug MetabolismToxic Organic Pollutants Impact

The environmental estrogen, nonylphenol, activates the constitutive androstane receptor

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Hernandez, J. P., Huang, W., Chapman, L. M., Chua, S., Moore, D. D., Baldwin, W. S.·2007·Toxicological Sciences

Abstract

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.

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  • Estrogen can both activate and inhibit CAR signaling depending on the ligand and its context; androgen inhibits CAR transcriptional activity.

    “It has been reported that estrogen can both activate and inhibit CAR signaling depending on the ligand and its context,66,67 whereas androgen inhibits CAR transcriptional activity,68”

    From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [67]

    The Results (page not available) show that the environmental estrogen nonylphenol activates CAR. The Discussion (page not available) also describes activation by several environmental estrogens, but our copy does not establish that estrogen inhibits CAR signaling in a different ligand context. The androgen clause is attached to a separate citation and is not judged here. (LLM, conf=0.85)

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  1. Fu X, Cooper SM, Delclos KB. Induction of hepatic enzyme expression by p-nonylphenol (NP) is modulated by diet in male Sprague-Dawley rats (#1829) The Toxicologist CD—An official Journal of the Society of Toxicology. 2006;90:S-1. [Google Scholar]
  2. Van der Hoeven TA, Coon MJ. Preparation and properties of partially purified cytochrome P450 and NADPH-cytochrome P450 reductase from rabbit liver microsomes. J. Biol. Chem. 1974;249:6302–6310. [PubMed] [Google Scholar]

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Authors
Hernandez, J. P., Huang, W., Chapman, L. M., Chua, S., Moore, D. D., & Baldwin, W. S.
Affiliations
  • City Of Hope National Medical Center (US)
  • The University of Texas at El Paso (US)
  • Baylor College of Medicine (US)
Corresponding author
Baldwin, W. S.
Venue
Toxicological Sciences
Published
2007-04-10
Volume
98
Issue
2
Pages
416-426
ISSN
  • 1096-0929 (ISSN-L)
  • 1096-6080
OpenAlex
W2151656156
Cited by
52
References
68
Citations by year
2026: 3 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 8 · 2015: 2 · 2012: 4
FWCI
3.29
Type
journal article
Language
en
Open access
Locations
  • Toxicological Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (GM008012-35, S06GM008012)
  • National Institute of Environmental Health Sciences (F31ES014113)
  • Division of Graduate Education
  • National Center for Research Resources (G12RR008124, G12 RR08124)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
Keywords
nonylphenol, nonylphenol ethoxylates, constitutive androstane receptor, xenoestrogens, Cyp2b10, CYP2B6, receptor nuclear translocation, androstanol, endocrine disruptors
MeSH terms
Cytochrome P450 Family 2, Pregnane X Receptor, Constitutive Androstane Receptor, Adult, Aged, Animals, Aryl Hydrocarbon Hydroxylases, Estrogens, Female, Humans, Liver, Mice, Transgenic, Middle Aged, Muscle Relaxants, Central, Oxidoreductases, N-Demethylating, Phenols, Receptors, Steroid, Steroid Hydroxylases, Transcription Factors, Zoxazolamine, Transcriptional Activation, Receptors, Cytoplasmic and Nuclear, Hepatocytes, Cell Line, Tumor, Mice, Rats, Endocrine Disruptors, Cytochrome P-450 CYP2B6

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