title: The mycotoxin, patulin, increases the expression of PXR and AhR and their target cytochrome P450s in primary cultured human hepatocytes.
abstract: The mycotoxin, patulin (PAT), which is frequently found in apples, grapes, oranges, pear, peaches, and in apple juices, has previously been shown to be cytotoxic, genotoxic, and mutagenic. In this study, we have investigated the effect of PAT on mRNA level of pregnane X receptor (PXR), constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AhR), and their corresponding target cytochrome P450s. Using primary cultures of adult human hepatocytes, we evaluated PAT cytotoxicity on hepatocytes after 24 hours of treatment. Real time reverse-transcriptase polymerase chain reaction procedure was employed to determine the effect of PAT on receptors (PXR, CAR, and AhR) and cytochrome (CYP3A4, 2B6, 3A5, 2C9, 1A1, and 1A2) genes. Our results showed that PAT reduced hepatocyte viability. At a noncytotoxic range of PAT concentrations, PAT induced an upregulation of the PXR gene in the three treated hepatocytes cultures, whereas CAR was overexpressed in only 1 treated liver. PXR gene induction was accompanied by the enhancement of CYP2B6, 3A5, 2C9, and 3A4 expression. PAT was also found to induce an overexpression of AhR and CYP1A1 and CYP1A2 mRNA expression. These findings suggested that PAT may activate PXR and/or CAR and AhR. However, further investigations are needed to confirm nuclear receptor activation by PAT and to elucidate the molecular mechanism of PAT action.
authors.affiliation: Laboratory of Research on Biologically Compatible Compounds, Faculty of Dentistry, Monastir, Tunisia.
authors.forename: Imen
authors.initials: I
authors.lastname: Ayed-Boussema
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Pascussi
authors.forename: Karima
authors.initials: K
authors.lastname: Rjiba
authors.forename: Patrick
authors.initials: P
authors.lastname: Maurel
authors.forename: Hassen
authors.initials: H
authors.lastname: Bacha
authors.forename: Wafa
authors.initials: W
authors.lastname: Hassen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D008156:Luciferases; D015394:Molecular Structure; D010365:Patulin / Q000737:chemistry / Q000633:toxicity*; D000077297:Pregnane X Receptor; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000255:Adenosine Triphosphate; D051792:Basic Helix-Loop-Helix Proteins; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases; D010365:Patulin; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C111235:AHR protein, human