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Modulation of MDR1 and CYP3A expression by dexamethasone: evidence for an inverse regulation in adrenals
E Sérée1, P H Villard, A Hevér
1UPRES-A CNRS 6032, EA 2194 Laboratory of Toxicology, Mediterranean University, 27 Boulevard J Moulin, Marseille, 13385, France. eric.seree@pharmacie.univ-mrs.fr
Abstract:
A strong overlap exists between gp170 and CYP3A substrates and inducers. In order to investigate a putative coregulation of MDR and CYPA gene expression, we measured their transcripts in human liver and after dexamethasone treatment in HepG2 cells or in different mouse tissues. In human liver, we observed no correlation between MDR1 and CYP3A4 expression, whereas these genes were coinduced by dexamethasone in HepG2 cells. In mouse liver treated with dexamethasone, mdr1b and Cyp3a were induced (5- and 2-fold, respectively). In adrenals, the main expressing gp170 tissue, Cyp3a, was increased while mdr1b was repressed (-51%). The expression of mdr1b increased in heart, brain, and colon and decreased in lung and kidney but Cyp3a was not detectable. In conclusion, human hepatic CYP3A4 and MDR1 are not corregulated but are coinducible. In vivo murine mdr1b and Cyp3a are coregulated by dexamethasone in liver and inversely regulated in adrenals.
Insights
Multidrug resistance (MDR) and cytochrome P450 3A (CYP3A) gene expression are not always correlated in humans but can be coinduced. In mice, these genes are coregulated in the liver but inversely regulated in adrenals.
Area of Science:
- Pharmacology
- Molecular Biology
- Genetics
Background:
- A known overlap exists between P-glycoprotein (gp170) and cytochrome P450 3A (CYP3A) substrates and inducers.
- Investigating coregulation of multidrug resistance (MDR) and CYP3A gene expression is crucial for understanding drug metabolism and transport.
Purpose of the Study:
- To investigate the coregulation of MDR1 and CYP3A gene expression in human liver and HepG2 cells.
- To examine the in vivo coregulation of mdr1b and Cyp3a in different mouse tissues following dexamethasone treatment.
Main Methods:
- Gene expression analysis of MDR1 and CYP3A4 in human liver samples.
- Dexamethasone induction studies in HepG2 cells.
- Quantitative analysis of mdr1b and Cyp3a transcripts in various mouse tissues.
Main Results:
- No correlation was observed between MDR1 and CYP3A4 expression in human liver.
- Dexamethasone coinduced MDR1 and CYP3A4 in HepG2 cells.
- In mice, dexamethasone induced mdr1b and Cyp3a in the liver, but inversely regulated them in adrenals. Tissue-specific regulation was observed in other organs.
Conclusions:
- Human hepatic CYP3A4 and MDR1 are not coregulated but are coinducible.
- Murine mdr1b and Cyp3a are coregulated by dexamethasone in the liver and inversely regulated in the adrenals, indicating tissue-specific regulatory mechanisms.