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Regulation of dioxin receptor function by omeprazole
N Dzeletovic1, J McGuire, M Daujat
1Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, S-171 77 Stockholm, Sweden.
The Journal of Biological Chemistry
|May 9, 1997
Summary
Omeprazole, a common anti-ulcer drug, activates the dioxin (aryl hydrocarbon) receptor in humans but not mice. This suggests omeprazole is a precursor for a new class of dioxin receptor agonists.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- The dioxin (aryl hydrocarbon) receptor (AhR) is an intracellular protein mediating cellular responses to dioxins and related pollutants.
- AhR functions as a ligand-activated transcription factor, regulating gene expression.
- Omeprazole, a widely used anti-ulcer medication, was investigated for its potential interaction with the AhR.
Purpose of the Study:
- To investigate the effects of omeprazole on dioxin receptor function.
- To determine if omeprazole acts as a ligand for the dioxin receptor.
- To explore the species-specific activation of the dioxin receptor by omeprazole.
Main Methods:
- Primary human and mouse hepatocytes were used to assess cytochrome P4501A1 mRNA expression.
- Reporter gene assays in human hepatoma cells and a receptor-deficient mouse hepatoma cell line were employed.
- A reconstituted yeast (Saccharomyces cerevisiae) model system was utilized to study receptor activation.
- In vitro ligand binding assays and analysis of mutant yeast strains with altered heat shock protein 90 (hsp90) levels were performed.
Main Results:
- Omeprazole induced cytochrome P4501A1 mRNA expression in human hepatocytes but not in mouse hepatocytes.
- Omeprazole activated transcription via the xenobiotic response element in human hepatoma cells.
- Omeprazole did not activate the human dioxin receptor in receptor-deficient mouse cells.
- Both human and mouse dioxin receptors were activated by omeprazole in a yeast model system.
- Omeprazole's activation of the dioxin receptor was dependent on specific ligand binding domain residues and hsp90 levels.
- The sulfoxide group of omeprazole was critical for dioxin receptor activation.
Conclusions:
- Omeprazole acts as a precursor for a novel class of dioxin receptor agonists.
- Omeprazole-mediated dioxin receptor activation is species-specific.
- The mechanism involves omeprazole acting as a bona fide ligand, albeit with unique activation characteristics.