Omeprazole is the prototypical proton pump inhibitor, available over-the-counter and in inexpensive generic formulations. It is promoted as a therapy for a range of disease states, from mild heartburn to aggressive H. pylori
gastritis, where it forms one component of the triple-agent therapy (clarithromycin, amoxicillin, and omeprazole) that is commonly used to eradicate H. pylori
]. However, it is increasingly well-recognized that omeprazole may also contribute to gastric gland toxicity. In this report we use a recently described gland viability assay to show that omeprazole is toxic to cells of the rabbit gastric gland at physiologically relevant doses (). We also demonstrate that this toxic effect occurs without the same disturbances to Zn2+
homeostasis that we have previously observed from a non-specific thiol oxidant, monochloramine () [11
Like monochloramine, the toxic effects of omeprazole can be reversed using both a thiol reducer (DTT) and a generic antioxidant (Vitamin C) ( & ), suggesting that omeprazole’s effect on cell viability is through its action as a thiol oxidant. However, while chelating zinc with TPEN protects the gastric gland from monochloramine, chelation does not prevent injury by omeprazole (). These data suggest that the two agents, while both acting as thiol oxidants, operate through different pathways to exert their toxic effects – monochloramine through a mechanism at least in part dependent on zinc-mediated toxicity, and omeprazole through a zinc-independent pathway.
The utility of Vitamin C to abrogate the toxicity of omeprazole may have clinical importance. Clinical studies have demonstrated that H. pylori
eradication is improved when supplemented with Vitamin C [31
] and that Vitamin C may decrease the total dose of antibiotic necessary for eradication [32
]. In addition, Vitamin C therapy has been shown to reduce histological and serological markers of inflammation in patients taking omeprazole as a monotherapy for H. pylori
]. Because omeprazole is now available over-the-counter for treatment of dyspepsia, such potentially inappropriate monotherapy is increasingly common [35
]. To our knowledge, this is the first report to identify a potential mechanism by which Vitamin C may provide benefit when co-administered with omeprazole in H. pylori
gastritis, by protecting the cells of the gastric gland against the toxic effects of both monochloramine and omeprazole. Because our studies suggest that pre-treatment with Vitamin C does not significantly impair the antisecretory potency of omeprazole, it may be a valuable adjunct to existing triple therapy for H. pylori
disease, or to monotherapy with omeprazole for non-infectious conditions.
In addition to potential direct effects on the cells of the gastric gland by Vitamin C, omeprazole users may benefit from Vitamin C supplementation for more indirect reasons. Inhibition of the proton pump has been shown to decrease active secretion of Vitamin C into the lumen of the stomach [36
] and to decrease plasma Vitamin C [37
]. Decreased availability of Vitamin C may have multiple deleterious effects. Luminal Vitamin C, in its active, ascorbic acid form, scavenges nitrites, converting them to nitric oxide and preventing their transformation into potentially mutagenic N-nitroso compounds [38
]. Vitamin C has also been demonstrated to increase absorption of non-heme iron [40
]. At higher pH, such as in the stomach of patients taking PPIs, ascorbic acid is oxidized to inactive dehydroascorbic acid, meaning that decreased Vitamin C in the gastric lumen of patient using PPIs is further impaired by the elevated pH of the gastric lumen [37
]. Oxidation of ascorbic acid has also been shown in H. pylori
infection, particularly in atrophic gastritis [42
]. This effect may be due to inflammatory mediators and to local pH elevation from ammonia produced by the bacterium [36
Taken together, these data suggest that omeprazole acts through a previously unappreciated thiol oxidation pathway to cause a decrease in cell viability of the rabbit gastric gland in vitro. A large number of potential targets for thiol oxidation exist within the cells of the gastric gland, as a wide range of intracellular proteins are susceptible to thiol oxidation. However, these data suggest that differential thiol oxidation occurs between monochloramine (which appears to act through a zinc-dependent pathway) and omeprazole (which does not depend on zinc to exert its toxic effect). That both monochloramine and omeprazole toxicity can be reversed with Vitamin C provides a mechanistic explanation for previously observed benefits to Vitamin C co-administration in H. pylori gastritis treated with omeprazole. Further elucidation of the mechanism of action and the benefits of ascorbic acid in treating and preventing gastritis may improve patient outcomes in the future.