Regulation of dioxin receptor function by omeprazole.

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Dzeletovic N, McGuire J, Daujat M, Tholander J, Ema M, Fujii-Kuriyama Y, Bergman J, Maurel P, Poellinger L

Regulation of dioxin receptor function by omeprazole.

J Biol Chem. 1997 May 9;272(19):12705-13.

PubMed ID

9139728 [ View in PubMed

]

Abstract

The intracellular dioxin (aryl hydrocarbon) receptor mediates signal transduction by dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) and related environmental pollutants and functions as a ligand-activated transcription factor. In this study we have examined the effects on dioxin receptor function of a potentially novel ligand, omeprazole, which is widely clinically used as a gastric anti-ulcer drug. In primary human hepatocytes omeprazole potently induced cytochrome P4501A1 mRNA expression, whereas this effect was not detected in mouse primary hepatocytes. In human hepatoma cells omeprazole was found to induce transcription of reporter genes via the xenobiotic response element that is recognized by the ligand-activated dioxin receptor. In contrast, the human dioxin receptor was not activated by omeprazole upon expression in a receptor-deficient mouse hepatoma cell line. In a reconstituted yeast (Saccharomyces cerevisiae) model system, however, both the mouse and human dioxin receptors were potently activated by omeprazole. Although omeprazole failed to displace dioxin in in vitro ligand binding assays, a residue within the ligand binding domain that is critical for dioxin binding in vitro was also critical for omeprazole responsiveness in vivo. Consistent with this observation, both omeprazole and dioxin responsiveness of the dioxin receptor was inhibited in mutant yeast cells expressing low levels of the molecular chaperone hsp90 that is critical for ligand binding activity. The sulfoxide group that is essential for formation of a planar conversion product of omeprazole was found to be critical for dioxin receptor activation. Taken together, these data suggest that omeprazole represents a precursor for a novel class of dioxin receptor agonists that are bona fide dioxin receptor ligands but generated in a strictly species-specific manner.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Omeprazole	Aryl hydrocarbon receptor	Protein	Humans	Unknown	Agonist	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Omeprazole	Approved Investigational Vet Approved	CYP1A1	1543	upregulated	Omeprazole results in increased expression of CYP1A1 mRNA	15q24.1