title: Poly- and perfluorinated compounds activate human pregnane X receptor.
abstract: Poly- and perfluorinated compounds (PFCs), which have been detected worldwide in human blood, surface water and house dust, are suspected to induce potential endocrine-disrupting hormonal effects. In this study, cell-based reporter gene assays were used to determine the activity of a variety of PFCs against the human pregnane X receptor (hPXR) to identify the critical structural feature of PFCs related to their hPXR activity. Molecular docking studies combined with site-directed mutagenesis were employed to investigate the mechanism by which PFCs interact with and activate hPXR. We found that all tested PFCs can activate hPXR. The hPXR activity of the PFCs correlates with the carbon chain length and the functional group of the chemicals. Hydrogen bonding was characteristic of the interaction between PFCs and hPXR. We also identified the key residues within the hPXR ligand-binding pocket responsible for PFC-hPXR interaction. The outcome of the present study threw a light on the mechanism by which PFCs activate hPXR. PFCs may pose some potential endocrine-disrupting hormonal effects via activation of hPXR.
authors.affiliation: School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China. Electronic address: zym@njmu.edu.cn.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Dong
authors.affiliation: School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Fan
authors.affiliation: School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Zhi-Lei
authors.initials: ZL
authors.lastname: Zhang
authors.affiliation: School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing 211166, China. Electronic address: yangxushu@njmu.edu.cn.
authors.forename: Xu-Shu
authors.initials: XS
authors.lastname: Yang
mesh_terms: D017738:Alkanesulfonic Acids / Q000633:toxicity*; D002210:Caprylates / Q000633:toxicity*; D052244:Endocrine Disruptors / Q000633:toxicity*; D005466:Fluorocarbons / Q000633:toxicity*; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D052244:Endocrine Disruptors; D005466:Fluorocarbons; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid
keywords: Human pregnane X receptor; PFCs; Poly- and perfluorinated compounds; Reporter gene assays; hPXR