Aflatoxins upregulate CYP3A4 mRNA expression in a process that involves the PXR transcription factor
Marcin Ratajewski1, Aurelia Walczak-Drzewiecka, Anna Sałkowska
1Laboratory of Transcriptional Regulation, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland.
Toxicology Letters
|June 7, 2011
Summary
Aflatoxins B1, M1, and G1 activate the Pregnane X receptor (PXR), a key regulator of liver metabolism. This finding reveals how these mycotoxins influence the expression of genes involved in their own detoxification.
Area of Science:
- Biochemistry
- Toxicology
- Molecular Biology
Background:
- Pregnane X receptor (PXR) is a nuclear hormone receptor superfamily member regulating liver metabolism.
- PXR is activated by diverse ligands, including drugs and environmental pollutants, influencing xenobiotic metabolism.
- PXR controls genes involved in biotransformation and xenobiotic disposition via DNA motif binding.
Purpose of the Study:
- To screen mycotoxins for their ability to activate PXR function in human liver cells.
- To investigate the impact of aflatoxins on PXR activation and downstream gene expression.
- To understand the role of PXR in the metabolic response to aflatoxin exposure.
Main Methods:
- Screening of mycotoxins for PXR activation in HepG2 human hepatocyte cell line.
- Analysis of CYP3A4 expression and PXR binding to the CYP3A4 promoter.
- Microarray analysis to assess global gene expression changes induced by aflatoxin B1.
Main Results:
- Aflatoxins B1, M1, and G1 were identified as PXR activators.
- Activation correlated with increased CYP3A4 expression and PXR occupancy on its promoter.
- Aflatoxin B1 upregulated PXR-dependent xenobiotic metabolism genes and downregulated cholesterologenesis genes.
Conclusions:
- Aflatoxin B1 activates PXR in human hepatocytes, modulating liver xenobiotic metabolism.
- Aflatoxins induce expression of PXR-dependent genes, including CYP3A4, involved in their own biotransformation.
- Aflatoxin B1 affects broader gene expression, impacting pathways like cholesterologenesis.
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