Omeprazole Does Not Cause Unscheduled DNA Synthesis in Rabbit Parietal Cells in Vitro

Abstract

Parietal cells from rabbit gastric mucosa, enriched to >90% purity, were used to study the effect of the H⁺K⁺-ATPase inhibitor omeprazole on DNA in vitro. In this preparation, omeprazole undergoes acid-catalyzed conversion to its active form, the sulfenamide, which subsequently binds to luminal SH groups of the H⁺K⁺-ATPase and thereby inhibits acid secretion. In the parietal cell fraction the S-phase inhibitor hydroxyurea (HU) decreased [³H]thymidine uptake by 40% as measured by liquid scintillation counting (LSC), presumably due to inhibition of scheduled DNA synthesis in contaminating stem cells. In the presence of HU, irradiation with ultraviolet light (UV) or treatment with the gastric carcinogen, l-methyl-3-nitro-l-nitrosoguanidine (MNNG) increased [³H]thymidine uptake by a factor of 5. Autoradiography of isolated, stimulated parietal cells showed that UV irradiation and MNNG treatment increased the average number of silver grains over the nuclei 18-fold and 4-fold, respectively. In contrast, treatment of histamine-stimulated parietal cells with omeprazole or ranitidine in concentrations 100 times the IC₅₀ value for inhibition of acid secretion in the parietal cells did not increase [³H]thymidine incorporation above the control levels, measured either by LSC or by autoradiography. Extracted DNA from stimulated parietal cells treated with [³H]omeprazole or [³H]MNNG showed no binding of [³H]-omeprazole but considerable binding of [³H]MNNG. It is concluded that parietal cells can undergo DNA repair, but there is no indication that omeprazole, or its acid-derived metabolites, should cause any damage to DNA, nor does it bind to DNA in its target cell, where the highest concentrations of omeprazole and its acid-derived products are found.

Key Words:

• Autoradiography
• DNA repair
• l-methyl-3-nitro-1-nitrosoguanidine
• mutagenicity
• omeprazole
• parietal cells