Unexpected Activation of PPIs Outside the Stomach May Explain Side Effects
A new study from the German Cancer Research Center (DKFZ) has discovered that proton pump inhibitors (PPIs) can be activated in an unexpected way—through interaction with zinc-binding proteins rather than solely by stomach acid. This finding may help explain some of the side effects that have long been associated with prolonged PPI use, such as an increased risk of cardiovascular diseases and dementia.
A study from the German Cancer Research Center (DKFZ) has revealed an unexpected activation mechanism for proton pump inhibitors (PPIs), drugs that are commonly used to treat acid-related conditions.
Research shows that PPIs can be activated by zinc-binding proteins in the body’s cells, independently of stomach acid. This discovery may help explain certain side effects linked to long-term use of these drugs.
Traditional Activation of Proton Pump Inhibitors
PPIs, such as pantoprazole, omeprazole, and rabeprazole, are prodrugs taken in an inactive form. They are normally activated in the acid-producing cells of the stomach through exposure to a high concentration of protons (hydrogen ions), which leads to inhibition of the proton pump and reduced acid production. This proton-dependent activation was previously believed to restrict PPIs’ effects to the stomach.
Discovery of Zinc-Mediated Activation
The research team, led by biochemist Tobias Dick and chemist Aubry Miller at DKFZ, used “click chemistry” to track rabeprazole in human cells under neutral pH conditions. They found that PPIs can be activated inside cells through interaction with zinc-binding proteins, even in the absence of high proton concentrations. This activation alters the structure and function of the affected proteins.
“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 of the DKFZ.
Implications for Side Effects
Long-term use of PPIs has been linked to increased risks of heart attack, stroke, dementia, and infections. The newly discovered zinc-mediated activation pathway provides insight into these side effects by demonstrating that PPIs can affect proteins even outside the stomach.
“These results open up new perspectives for a better understanding of the side effects of PPIs“ says Tobias Dick.