A food contaminant ochratoxin A suppresses pregnane X receptor (PXR)-mediated CYP3A4 induction in primary cultures of human hepatocytes

Toxicology
Aneta Doricakova, Radim Vrzal

Abstract

Ochratoxin A (OCHA) is a mycotoxin, which can be found in food such as coffee, wine, cereals, meat, nuts. Since it is absorbed via gastrointestinal tract, it is reasonable to anticipate that the liver will be the first organ to which OCHA comes into the contact before systemic circulation. Many xenobiotics are metabolically modified after the passage of the liver to biologically more active substances, sometimes with more harmful activity. Promoting own metabolism is often achieved via transcriptional regulation of biotransformation enzymes through ligand-activated transcription factors. Pregnane X receptor (PXR) belongs to such a group of regulators and it was demonstrated to be activated by many compounds of synthetic as well as natural origin. Our intention was to investigate if OCHA is capable of activating the PXR with consequent induction of PXR-regulated CYP3A4 gene. We found that OCHA does not activate PXR but displays antagonist-like behavior when combined with rifampicin (RIF) in gene reporter assay in human embryonal kidney cells (Hek293T). It was very weak inducer of CYP3A4 mRNA in primary cultures of human hepatocytes and it antagonized RIF-mediated CYP3A4 induction of mRNA as well as protein. In addition, it cause...Continue Reading

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Citations

Dec 29, 2016·European Journal of Clinical Pharmacology·Sukumaran Sanjay, Chandrashekaran Girish
Sep 22, 2017·Current Medicinal Chemistry·Juan Pablo RigalliJohanna Weiss
Nov 5, 2020·Cells·Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin
Dec 18, 2019·Mutation Research. Reviews in Mutation Research·Yuxiao LiaoWei Yang
May 8, 2021·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Liye ZhuWentao Xu
Aug 5, 2021·Critical Reviews in Food Science and Nutrition·Haonan RuanMeihua Yang

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