title: Transcriptional regulation of human paraoxonase 1 by PXR and GR in human hepatoma cells.
abstract: Human paraoxonase 1 (PON1) is A-esterase synthesized in the liver and secreted into the plasma, where it associates with HDL. PON1 acts as an antioxidant preventing lipid oxidation and detoxifies a wide range of substrates, including organophosphate compounds. The variability of PON1 (enzyme activity/serum levels) has been attributed to internal and external factors. However, the molecular mechanisms involved in the transcriptional regulation of PON1 have not been well-studied. The aim of this study was to evaluate and characterize the transcriptional activation of PON1 by nuclear receptors (NR) in human hepatoma cells. In silico analysis was performed on the promoter region of PON1 to determine the response elements of NR. Real-time PCR was used to evaluate the effect of specific NR ligands on the mRNA levels of genes regulated by NR and PON1. The results indicated that NR response elements had 95% homology to pregnenolone (PXR), glucocorticoids (GR), retinoic acid (RXR) and peroxisomes proliferator-activated receptor alpha (PPARα). Treatments with Dexamethasone (GR ligand), Rifampicin (PXR ligand) and TCDD (AhR ligand) increased the mRNA levels of PON1 at 24 and 48 h. We showed that the activation of GR by Dexamethasone results in PON1 gene induction accompanied by an increase in activity levels. In conclusion, these results demonstrate that GR regulates PON1 gene transcription through directly binding to NR response elements at -95 to -628 bp of the PON1 promoter. This study suggests new molecular mechanisms for the transcriptional regulation of PON1 through a process involving the activation of PXR.
authors.affiliation: Laboratorio de Contaminación y Toxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Nayarit, Mexico; Posgrado en Ciencias Biológico Agropecuarias, Universidad Autónoma de Nayarit, Tepic, Nayarit, Mexico. Electronic address: aguilas_bd@hotmail.com.
authors.forename: N
authors.initials: N
authors.lastname: Ponce-Ruiz
authors.affiliation: Laboratorio de Contaminación y Toxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Nayarit, Mexico. Electronic address: aerg81@gmail.com.
authors.forename: A E
authors.initials: AE
authors.lastname: Rojas-García
authors.affiliation: Laboratorio de Contaminación y Toxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Nayarit, Mexico. Electronic address: bravis13@hotmail.com.
authors.forename: B S
authors.initials: BS
authors.lastname: Barrón-Vivanco
authors.affiliation: Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México, D.F., Mexico. Electronic address: gazuela@cinvestav.mx.
authors.forename: G
authors.initials: G
authors.lastname: Elizondo
authors.affiliation: Laboratorio de Contaminación y Toxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Nayarit, Mexico. Electronic address: yael010@hotmail.com.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Bernal-Hernández
authors.affiliation: Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México, D.F., Mexico. Electronic address: mejiagarciaa@gmail.com.
authors.forename: A
authors.initials: A
authors.lastname: Mejía-García
authors.affiliation: Laboratorio de Contaminación y Toxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Nayarit, Mexico. Electronic address: irmartha@hotmail.com.
authors.forename: I M
authors.initials: IM
authors.lastname: Medina-Díaz
mesh_terms: D043303:Aryldialkylphosphatase / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D011284:Pregnenolone / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
chemical_list: D005938:Glucocorticoids; D011284:Pregnenolone; D003907:Dexamethasone; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human
keywords: HepG2 cell; Nuclear receptors; Paraoxonase 1; Transcription