{"doi":"10.1016/j.jcmgh.2020.04.012","title":"Tamoxifen Acts as a Parietal Cell Protonophore","abstract":"Oxyntic atrophy, the loss of gastric parietal cells, is a critical precursor of metaplasia in the stomach. In the case of humans, Helicobacter pylori infection induces loss of parietal cells from the corpus of the stomach over years, while 6–12 months of Helicobacter infection is required to induce oxyntic atrophy in rodents.1Fox J.G. et al.Gastroenterology. 1996; 110: 155-166Abstract Full Text PDF PubMed Scopus (164) Google Scholar In mice, acute models of parietal cell loss have helped distinguish key steps in the induction of chief cell reprogramming into metaplasia. These studies initially used the drug DMP-777, which was demonstrated to function as a parietal cell secretory membrane protonophore using assay of H/K-ATPase–dependent proton gradients in isolated rabbit tubulovesicles.2Goldenring J.R. et al.Gastroenterology. 2000; 118: 1080-1093Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar DMP-777 did not directly inhibit the proton pump activity. Treatment with DMP-777 caused rapid parietal cell loss in both mice and rats over 3 days, leading to development of spasmolytic polypeptide-expressing metaplasia.2Goldenring J.R. et al.Gastroenterology. 2000; 118: 1080-1093Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar,3Nomura S. et al.Am J Physiol Gastrointest Liver Physiol. 2004; 288: G362-G375Crossref Scopus (120) Google Scholar Pretreatment of rats with proton pump inhibitors blunted the ability of DMP-777 to induce oxyntic atrophy.4Ogawa M. et al.Dig Dis Sci. 2006; 51: 431-439Crossref PubMed Scopus (11) Google Scholar Similar findings were seen for a number of molecular cousins of DMP-777, including L635.5Nam K.T. et al.Gastroenterology. 2010; 139: 2028-2037Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar While DMP-777 induces oxyntic atrophy without a prominent immune response, because of its coordinate action as a neutrophil elastase inhibitor, L635 lacks this action against elastase and elicits parietal cell loss and an exuberant immune response.5Nam K.T. et al.Gastroenterology. 2010; 139: 2028-2037Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar In more recent years, other studies have demonstrated the ability of tamoxifen administration (especially intraperitoneal doses of 5 mg or greater) to also induce parietal cell loss.6Huh W.J. et al.Gastroenterology. 2012; 142: 21-24.e7Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar As with DMP-777, pretreatment of mice with proton pump inhibitors ameliorated the effects of tamoxifen to induce parietal cell loss.6Huh W.J. et al.Gastroenterology. 2012; 142: 21-24.e7Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar However, no studies have directly assayed the effects of tamoxifen as a parietal cell protonophore. We have therefore sought to compare the effects of tamoxifen with those of DMP-777 and L635 on acid sequestration in parietal cell tubulovesicles. Parietal cell tubulovesicles were isolated from rabbit stomach mucosa using standard protocols and tubulovesicles layering above 20% sucrose in gradient centrifugation were utilized as the tightest tubulovesicle membranes (see supplementary methods).7Crothers Jr., J.M. et al.Am J Physiol. 1993; 265: G231-G241PubMed Google Scholar The fluorescence of acridine orange was assayed in tubulovesicles using induction of pumping in the presence of adenosine triphosphate and valinomycin. Activation of acid pumping into tubulovesicles causes a rapid quenching of acridine orange fluorescence indicative of pumping of acid into the lumen of tubulovesicles (Figure 1). After the establishment of the proton gradient in tubulovesicles, tamoxifen, DMP-777, or L635 were added in concentrations from 0.1 to 10 μM and effects on the quenching of acridine orange were assayed (Figure 1). At concentrations from 1 to 10 μM, all 3 drugs caused a rapid decrease in acridine orange fluorescence, indicative of disruption of the proton gradient. 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Goldenring","orcid":"0000-0002-7833-2940","position":3,"is_corresponding":false},{"id":375665,"name":"ElizabethL. Manning","orcid":null,"position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-18T21:43:32.585486Z","pmid":"32361017","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}