Regulation of Dioxin Receptor Function by Omeprazole

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.

Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: Evidence for both genetic and environmental influences

“…36 While 3-methylcholanthrene obviously has no potential therapeutic utility, less hazardous agents are available that induce hepatic metabolizing enzymes by the same mechanism. 37,38 Furthermore, the risk of adverse effects associated with the long-term use of these agents may be outweighed by the risk of developing life-threatening kernicteric encephalopathy.…”

Influence of Omeprazole on Multidrug Resistance Protein 3 Expression in Human Liver

“…First, activation of the Ah receptor pathway mediates CYP1A1 induction by omeprazole (Daujat et al, 1992;Backlund et al, 1997;Dzeletovic et al, 1997). Second, dioxinresponsive elements to which the Ah receptor/Arnt heterodimer may bind have been identified in the 5Ј-flanking region of human MRP3 (Takada et al, 2000).…”

Microbial Metabolites of Omeprazole Activate Murine Aryl Hydrocarbon Receptor In Vitro and In Vivo

“…OME-mediated CYP1A1 induction was identified in human primary hepatocytes and hepatoma cells, but not in mouse cells (Kikuchi et al, 1995). Meanwhile, in the yeast reconstituted AhR assay system, OME activated both mouse and human AhRs (Dzeletovic et al, 1997). Therefore, the response to OME seems to be independent of the animal species from which AhR originates.…”