Omeprazole and lansoprazole enantiomers induce CYP3A4 in human hepatocytes and cell lines via glucocorticoid receptor and pregnane X receptor axis.

Aneta Novotna,Zdenek Dvorak,Hans-Joachim Lehmler

doi:10.1371/journal.pone.0105580

Aneta Novotna, Zdenek Dvorak + Show 1 more

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https://doi.org/10.1371/journal.pone.0105580

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Abstract

Benzimidazole drugs lansoprazole and omeprazole are used for treatment of various gastrointestinal pathologies. Both compounds cause drug-drug interactions because they activate aryl hydrocarbon receptor and induce CYP1A genes. In the current paper, we examined the effects of lansoprazole and omeprazole enantiomers on the expression of key drug-metabolizing enzyme CYP3A4 in human hepatocytes and human cancer cell lines. Lansoprazole enantiomers, but not omeprazole, were equipotent inducers of CYP3A4 mRNA in HepG2 cells. All forms (S-, R-, rac-) of lansoprazole and omeprazole induced CYP3A4 mRNA and protein in human hepatocytes. The quantitative profiles of CYP3A4 induction by individual forms of lansoprazole and omeprazole exerted enantiospecific patterns. Lansoprazole dose-dependently activated pregnane X receptor PXR in gene reporter assays, and slightly modulated rifampicin-inducible PXR activity, with similar potency for each enantiomer. Omeprazole dose-dependently activated PXR and inhibited rifampicin-inducible PXR activity. The effects of S-omeprazole were much stronger as compared to those of R-omeprazole. All forms of lansoprazole, but not omeprazole, slightly activated glucocorticoid receptor and augmented dexamethasone-induced GR transcriptional activity. Omeprazole and lansoprazole influenced basal and ligand inducible expression of tyrosine aminotransferase, a GR-target gene, in HepG2 cells and human hepatocytes. Overall, we demonstrate here that omeprazole and lansoprazole enantiomers induce CYP3A4 in HepG2 cells and human hepatocytes. The induction comprises differential interactions of omeprazole and lansoprazole with transcriptional regulators PXR and GR, and some of the effects were enantiospecific. The data presented here might be of toxicological and clinical importance, since the effects occurred in therapeutically relevant concentrations.

Highlights

Many clinically used drugs contain in their chemical structure chiral atom, they exist in 2n conformations – enantiomers, where n stands for number of chiral centers in the molecule
In the current paper we examined the effects of lansoprazole and omeprazole enantiomers on the expression of CYP3A4 in human hepatocytes and human cancer cell lines, and on transcriptional activity of pregnane X receptor (PXR) and glucocorticoid receptor (GR) in transgenic cell lines
Human hepatoma HepG2 cells, intestinal cancer cells LS174T and primary human hepatocytes were treated with rifampicin (RIF; 10 mM), vehicle (DMSO; 0.1% V/V), S-enantiomers. Enantiopure drug Esomeprazole (S-OME), R-OME, rac-OME, S-LAN, r3">3]. FDA has approved Dexlansoprazole (R-LAN) and rac-LAN at concentrations ranging from 1 mM to 250 mM for 24 h and 48 h

Summary

Introduction

Many clinically used drugs contain in their chemical structure chiral atom, they exist in 2n conformations – enantiomers, where n stands for number of chiral centers in the molecule. The ratio between pharmacokinetic parameters of eutomer and dystomer is called eudysmic ratio. The facts that eudysmic ratio is largely different from ‘‘1’’ justifies the use of enantiopure drugs in clinical practice, which was the case of benzimidazole proton pump inhibitors omeprazole (OME) and lansoprazole (LAN). Both compounds contain the asymmetric chiral sulfur atom in their chemical structure and they exist in form R- and S-enantiomers. FDA has approved Dexlansoprazole (R-LAN) in 2009 as an enatiopure drug for treatment of gastro esophageal reflux disease [4,5]

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