Acid blockers gone astray
Acid blockers from the group of proton pump inhibitors (PPIs) are popular drugs that prevent and alleviate stomach complaints. PPIs are activated at the acid-producing cells of the stomach and block acid production there. Researchers from the German Cancer Research Center (DKFZ) made the surprising discovery that zinc-carrying proteins, which are found in all cells, can also activate PPIs - without the presence of stomach acid. The result could be a key to understanding the side effects of PPIs.
Too much stomach acid can cause heartburn, but also chronic complaints, such as gastritis or even a stomach ulcer. For treatment, the doctor usually prescribes a proton pump inhibitor (PPI), often referred to as an acid blocker. Examples include the active ingredients pantoprazole, omeprazole or rabeprazole. PPIs bind and block an enzyme in the parietal cells of the stomach, the so-called proton pump, and thus effectively reduce gastric acid production.
PPIs are so-called prodrugs, i.e. they are taken as an inactive precursor. Their activation into the actual active ingredient is triggered by protons. The presence of many protons is the hallmark of an acid. The proton pump in the intestinal wall supplies the protons for the acidification of the gastric fluid. As there is a particularly high concentration of protons in the immediate vicinity of the proton pump, the PPIs are activated locally. The proton-dependent activation ensures that PPIs practically only attack and paralyze the proton pump, at least according to previous doctrine.
Even though the temporary use of PPIs is generally very well tolerated and is considered harmless, long-term use harbors health risks. Among other things, the specialist literature discusses a possible increased risk of heart attacks, strokes, dementia and susceptibility to infections. The question therefore arises as to whether PPIs are also activated outside the stomach and influence other proteins, i.e. independently of an environment with a high proton concentration.
Researchers led by biochemist Tobias Dick and chemist Aubry Miller, both at the DKFZ, have jointly addressed this question. They used so-called click chemistry, a strategy for labeling molecules that was awarded the Nobel Prize three years ago. They used it to track the active substance rabeprazole, a typical representative of PPIs, in human cells in the culture dish, away from an acidic environment.
The team made a surprising observation: the PPI was activated in the pH-neutral interior of the cells, where it combined with dozens of proteins. Further analysis showed that these were zinc-binding proteins. "This led us to the hypothesis that protein-bound zinc can lead to the activation of PPIs, regardless of the presence of protons," explains biologist Teresa Marker, first author of the publication.
In the course of further investigations, the researchers were able to show that protein-bound zinc actually forms a chemical bond with the PPI, which then leads to the activation of the PPI. The activated PPI is highly reactive and binds to the zinc-carrying protein on site. This in turn disrupts the structure and function of the attacked protein.
"From a chemical point of view, this result makes sense because zinc can mimic the effect of protons and behave like an acid," explains chemist Aubry Miller from the DKFZ.
Among the zinc-carrying proteins that were most strongly attacked by the PPI, some have a function in the immune system. Whether the newly discovered activation mechanism is linked to the known or suspected side effects of PPIs, however, still needs to be investigated in further studies. "These results open up new perspectives to better understand the side effects of PPIs," summarizes Tobias Dick.
Note: This article has been translated using a computer system without human intervention. LUMITOS offers these automatic translations to present a wider range of current news. Since this article has been translated with automatic translation, it is possible that it contains errors in vocabulary, syntax or grammar. The original article in German can be found here.
Original publication
Teresa Marker, Raphael R. Steimbach, Cecilia Perez-Borrajero, Marcin Luzarowski, Eric Hartmann, Sibylle Schleich, Daniel Pastor-Flores, Elisa Espinet, Andreas Trumpp, Aurelio A. Teleman, Frauke Gräter, Bernd Simon, Aubry K. Miller, Tobias P. Dick; "Site-specific activation of the proton pump inhibitor rabeprazole by tetrathiolate zinc centres"; Nature Chemistry, 2025-2-20
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