Highly potent binding and inverse agonist activity of bisphenol A derivatives for retinoid-related orphan nuclear receptor RORγ

Mitsuhiro Nishigori, Takeru Nose, Yasuyuki Shimohigashi

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The plastic chemical bisphenol A (BPA) has recently been suspected to be a base structure of endocrine disrupting chemicals, which achieve their adverse effects by interfering with human nuclear receptors. For instance, BPA, bisphenol AF, and tetrabromo- or tetrachloro-BPA (X 4-BPA) have been characterized as binders for ERRγ, ER, and PPARγ, respectively. This ongoing string of findings has led to apprehension that some other BPA derivatives might also perturb important human nuclear receptors. The retinoid-related orphan receptor RORγ has been strongly suspected to be a target of highly hydrophobic chemical substances because of its extreme affinity for lipophilic sterols. In the present study, we tested a series of BPA derivatives for their ability to bind to RORγ, and identified two distinctly potent derivatives having isopropyl or sec-butyl groups at positions adjacent to the BPA-4-hydroxyl group. In particular, di-sec-butyl-BPA has emerged as a considerably potent ligand (IC 50=146nM). In the reporter gene assay, these compounds suppressed the basal constitutive transcriptional activity originally induced by wild-type RORγ. The present results strongly suggested that RORγ, and perhaps also RORα and RORβ, binds highly hydrophobic and sterically hindered chemical substances, inducing some unspecified physiological and biochemical disruptions.

Original languageEnglish
Pages (from-to)205-211
Number of pages7
JournalToxicology Letters
Volume212
Issue number2
DOIs
Publication statusPublished - Jul 20 2012

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Orphan Nuclear Receptors
Retinoids
Derivatives
Cytoplasmic and Nuclear Receptors
Endocrine Disruptors
Peroxisome Proliferator-Activated Receptors
bisphenol A
Sterols
Reporter Genes
Hydroxyl Radical
Plastics
Binders
Assays
Genes
Ligands

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Highly potent binding and inverse agonist activity of bisphenol A derivatives for retinoid-related orphan nuclear receptor RORγ. / Nishigori, Mitsuhiro; Nose, Takeru; Shimohigashi, Yasuyuki.

In: Toxicology Letters, Vol. 212, No. 2, 20.07.2012, p. 205-211.

Research output: Contribution to journalArticle

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