title: Environmental pollutants parathion, paraquat and bisphenol A show distinct effects towards nuclear receptors-mediated induction of xenobiotics-metabolizing cytochromes P450 in human hepatocytes.
abstract: Environmental pollutants parathion, bisphenol A and paraquat were not systematically studied towards the effects on the expression of phase I xenobiotics-metabolizing cytochromes P450 (CYPs). We monitored their effects on the expression of selected CYPs in primary cultures of human hepatocytes. Moreover, we investigated their effects on the receptors regulating these CYPs, particularly arylhydrocarbon receptor (AhR), pregnane X receptor (PXR) and glucocorticoid receptor (GR) by gene reporter assays. We found that parathion and bisphenol A are the activators of AhR. Moreover, they are the inducers of CYP1A1 mRNA in hepatoma cells HepG2 as well as in human hepatocytes by AhR-dependent mechanism via formation of AhR-DNA-binding complex, as revealed by gel shift assay. All three compounds possessed anti-glucocorticoid action as revealed by GR-dependent gene reporter assay and a decline in tyrosine aminotransferase (TAT) gene expression in human hepatocytes. Moreover, parathion and bisphenol A are the activators of PXR and inducers of CYP3A4 mRNA and protein in the primary cultures of human hepatocytes. In conclusion, the studied compounds displayed distinct activities towards nuclear receptors involved in many biological processes and these findings may help us to better understand their adverse actions in pathological states followed after their exposure.
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic. Electronic address: radim.vrzal@email.cz.
authors.forename: Radim
authors.initials: R
authors.lastname: Vrzal
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Zenata
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
authors.forename: Aneta
authors.initials: A
authors.lastname: Doricakova
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Dvorak
mesh_terms: D001559:Benzhydryl Compounds / Q000378:metabolism / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D004790:Enzyme Induction; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D050216:Metabolic Detoxication, Phase I; D008875:Middle Aged; D010269:Paraquat / Q000378:metabolism / Q000633:toxicity; D010278:Parathion / Q000378:metabolism / Q000633:toxicity; D010636:Phenols / Q000378:metabolism / Q000633:toxicity; D000077297:Pregnane X Receptor; D061251:Primary Cell Culture; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015262:Xenobiotics / Q000378:metabolism / Q000633:toxicity*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D003577:Cytochrome P-450 Enzyme System; D004785:Environmental Pollutants; D010269:Paraquat; D010278:Parathion; D010636:Phenols; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D015262:Xenobiotics; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: AhR; CYP3A4; Human hepatocytes; PXR; TAT