ArticleToxicological sciences : an official journal of the Society of Toxicology2011
Selective phthalate activation of naturally occurring human constitutive androstane receptor splice variants and the pregnane X receptor.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.
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Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it, 94 citations in OpenAlex.
- An updated systematic review on the possible effect of nonylphenol on male fertility.Environmental science and pollution research international · 2017Pooled it
- A Universal Plasticizer Alkylsulfonic Phenyl Ester Activates Pregnane X Receptor to Increase Intestinal Cholesterol Uptake.International journal of molecular sciences · 2026Article
- The EDC mixture "NeuroMix" alters neuroendocrine physiology, fatty food preference, and the central reward transcriptome.Endocrinology · 2026Article
- Review
- Endocrine-disrupting chemicals as prostate carcinogens.Nature reviews. Urology · 2025Review
- Intrahepatic cholestasis of pregnancy.Nature reviews. Disease primers · 2025Review
- Computationally-Assisted Discovery and Assignment of a New Class of 6/6/5/5 Fused-Ring Diterpene Acting as Pregnane X Receptor Ligands fromJournal of natural products · 2024Article
- An insight into carcinogenic activity and molecular mechanisms of Bis(2-ethylhexyl) phthalate.Frontiers in toxicology · 2024Article
- Constitutive Androstane Receptor Agonist, TCPOBOP: Maternal Exposure Impairs the Growth and Development of Female Offspring in Mice.International journal of molecular sciences · 2023Article
- Are BPA Substitutes as Obesogenic as BPA?International journal of molecular sciences · 2022Review
- Article
- Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice.Environmental health perspectives · 2021Article
- Mechanistic insight into toxicity of phthalates, the involved receptors, and the role of Nrf2, NF-κB, and PI3K/AKT signaling pathways.Environmental science and pollution research international · 2021Review
- Sources of Interindividual Variability.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Review
- Review
- Xenobiotic Receptors and Their Mates in Atopic Dermatitis.International journal of molecular sciences · 2019Review
- Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors.Scientific reports · 2019Article
- Constitutive androstane receptor 1 is constitutively bound to chromatin and 'primed' for transactivation in hepatocytes.Molecular pharmacology · 2019Article
- Impact of CAR Agonist Ligand TCPOBOP on Mouse Liver Chromatin Accessibility.Toxicological sciences : an official journal of the Society of Toxicology · 2018Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Phthalates and other endocrine-disruptive chemicals are manufactured in large quantities for use as plasticizers and other commercial applications, resulting in ubiquitous human exposure and thus, concern regarding their toxicity. Innate defense against small molecule exposures is controlled in large part by the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). The human CAR gene undergoes multiple alternative splicing events resulting in the CAR2 and CAR3 variant receptors. Recent studies from our laboratory show that CAR2 is potently and specifically activated by di(2-ethylhexyl) phthalate (DEHP). We hypothesized that alternative splicing is a mechanism for increasing CAR's functional diversity, broadening the human receptors' repertoire of response to environmental xenobiotics. In these studies, we examine the interaction of alternatively spliced CARs and PXR with a range of suspected endocrine disruptors, including phthalates, bisphenol A (BPA), and 4-N-nonylphenol (NP). Transactivation and two-hybrid studies in COS-1 cells revealed differential selectivity of endocrine-disrupting chemicals for the variant CAR and PXR. Ex vivo studies showed DEHP and di-isononyl phthalate potently induced CYP2B6 and CYP3A4 expression in human hepatocytes. Mutation analysis of CAR2, in silico modeling, and ligand docking studies suggested that the SPTV amino acid insertion of CAR2 creates a unique ligand-binding pocket. Alternative gene splicing results in variant CAR receptors that selectively recognize phthalates and BPA. The interaction of phthalates with CAR and PXR suggests a xenobiotic response that is complex and biologically redundant.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.