Abstract
Proton pump inhibitors omeprazole and lansoprazole contain chiral sulfur atom and they are administered as a racemate, i.e. equimolar mixture of S- and R-enantiomers. The enantiopure drugs esomeprazole and dexlansoprazole have been developed and introduced to clinical practice due to their improved clinical and therapeutic properties. Since omeprazole and lansoprazole are activators of aryl hydrocarbon receptor (AhR) and inducers of CYP1A genes, we examined their enantiospecific effects on AhR-CYP1A pathway in human cancer cells and primary human hepatocytes. We performed gene reporter assays for transcriptional activity of AhR, RT-PCR analyses for CYP1A1/2 mRNAs, western blots for CYP1A1/2 proteins and EROD assay for CYP1A1/2 catalytic activity. Lansoprazole and omeprazole enantiomers displayed differential effects on AhR-CYP1A1/2 pathway. In general, S-enantiomers were stronger activators of AhR and inducers of CYP1A genes as compared to R-enantiomers in lower concentrations, i.e. 1–10 µM for lansoprazole and 10–100 µM for omeprazole. In contrast, R-enantiomers were stronger AhR activators and CYP1A inducers than S-enantiomers in higher concentrations, i.e. 100 µM for lansoprazole and 250 µM for omeprazole. In conclusion, we provide the first evidence of enantiospecific effects of omeprazole and lansoprazole on AhR signaling pathway.
Highlights
Proton pump inhibitors (PPIs) including omeprazole, lansoprazole, pantoprazole, rabeprazole and others are used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease as well as the eradication of Helicobacter pylori as a part of combination regimens
We examined a capability of omeprazole and lansoprazole to induce CYP1A1 and CYP1A2 mRNA and protein in primary human hepatocytes, which is a more physiological and metabolically competent cell model
Since omeprazole and lansoprazole are activators of aryl hydrocarbon receptor (AhR) and inducers of CYP1A genes, we examined their enantiospecific effects on AhR-CYP1A pathway in human cancer cells and primary human hepatocytes
Summary
Proton pump inhibitors (PPIs) including omeprazole, lansoprazole, pantoprazole, rabeprazole and others are used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease as well as the eradication of Helicobacter pylori as a part of combination regimens. These drugs block the gastric H, KATPase by covalent binding at different cysteine residues and inhibit gastric acid secretion [1,2]. PPIs are weak bases administered most frequently orally in form of pro-drug Their activation takes place in the acid space of the secretory canaliculus of the stimulated parietal cells resulting in the conversion to reactive sulfenamids [3,4]. Since R-enantiomer of lansoprazole, dexlansoprazole, constitutes more than 80% of circulating drug after oral administration of racemic drug, provides lower clearance and 5-fold greater systemic exposure than the S-enantiomer, FDA has approved dexlansoprazole in 2009 as an enatiopure drug for treatment of GERD [8,9]
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