Differential Effects of Omeprazole and Lansoprazole Enantiomers on Aryl Hydrocarbon Receptor in Human Hepatocytes and Cell Lines

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.

Omeprazole induces heme oxygenase-1 in fetal human pulmonary microvascular endothelial cells via hydrogen peroxide-independent Nrf2 signaling pathway

“…Moreover, we have shown that OM is a potent inducer of HO-1 enzyme, when we compared against DMSO-treated cells. The concentration of OM used in this study was comparable to those used in previous studies (Jin et al , 2014; Novotna et al , 2014). More importantly, we included the blood concentrations that are observed in humans following OM therapy (Cederberg et al , 1992).…”

Omeprazole and Lansoprazole Enantiomers Induce CYP3A4 in Human Hepatocytes and Cell Lines via Glucocorticoid Receptor and Pregnane X Receptor Axis

“…Prior to the gene reporter assays, cytotoxicity of tested compounds in LS174T cells after 24 h of incubation was assessed by conventional MTT test (cytotoxicity of OME and LAN in HepG2 cells and human hepatocytes was tested elsewhere [7]). We did not observe significant decline in viability of LS174T cells by LAN (up to 100 µM) and OME (up to 250 µM) (Figure 3; upper panels).…”

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

“…Strikingly the AhR agonistic activity of both 35 and 36 does not conform to the same enantiomeric pattern as noted with their PPI activity. This activity differentiation is attributed to enantiomeric effects of the stereoisomers on AhR activation and CYP1A induction . With these benzimidazoles, the S‐enantiomers displayed stronger AhR activation and CYP1A induction at lower concentrations (1‐10 μM for lansoprazole ( 36 ) and 10‐100 μM for omeprazole ( 35 )), while the R‐enantiomers maintained better activity at higher concentrations (100 μM for lansoprazole ( 36 ) and 250 μM for omeprazole ( 35 )).…”