Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of lysosomal enzyme activities by proton pump inhibitors

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Proton pump inhibitors (PPIs) are pro-drugs requiring an acidic pH for activation. The specificity of PPI toward the proton pump is mainly due to the extremely low pH at the parietal cell canalicular membrane where the pump is located. Reactivity of PPIs was also observed in moderately acidic environments like the renal collecting duct. But no PPI effect on lysosomal enzymes has been observed possibly because the previous studies were performed with liver tissue, where PPIs are metabolized.

Methods

The reactivity of PPIs (omeprazole, lansoprazole and pantoprazole) with a cysteine-containing peptide was analyzed by mass spectrometry, and the impact of PPIs on lysosomal enzymes was evaluated in cultured cells and mice. The effect of PPIs on the immune system was examined with a mouse tumor immunotherapy model.

Results

Incubation of a cysteine-containing peptide with PPIs at pH5 led to the conversion of most of the peptide into PPI-peptide adducts. Dose dependent inhibition of lysosomal enzyme activities by PPIs was observed in cultured cells and mouse spleen. Further, PPI counteracted the tumor immunotherapy in a mouse model.

Conclusions

Our data support the hypothesis that many of the PPI adverse effects are caused by systematically compromised immunity, a result of PPI inhibition of the lysosomal enzymes. This novel mechanism complements the existing mechanisms in explaining the increased incidence of tumorigenesis and infectious diseases among PPI users and underlie the ongoing concern about the overuse of PPIs in adult and pediatric populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AP:

Acid phosphatase

CID:

Collision-induced dissociation

GERD:

Gastroesophageal reflux disease

MPO:

Myeloperoxidase

NAG:

β-N-acetylglucosaminidase

PPIs:

Proton pump inhibitors

References

  1. Bamberg P, Caswell CM, Frame MH, Lam SK, Wong EC. A meta-analysis comparing the efficacy of omeprazole with H2-receptor antagonists for acute treatment of duodenal ulcer in Asian patients. J Gastroenterol Hepatol. 1992;7:577–85.

    Article  CAS  PubMed  Google Scholar 

  2. Eriksson S, Langstrom G, Rikner L, Carlsson R, Naesdal J. Omeprazole and H2-receptor antagonists in the acute treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis: a meta-analysis. Eur J Gastroenterol Hepatol. 1995;7:467–75.

    CAS  PubMed  Google Scholar 

  3. Gisbert JP, Gonzalez L, Calvet X, Roque M, Gabriel R, et al. Proton pump inhibitors versus H2-antagonists: a meta-analysis of their efficacy in treating bleeding peptic ulcer. Aliment Pharmacol Ther. 2001;15:917–26.

    Article  CAS  PubMed  Google Scholar 

  4. Gisbert JP, Khorrami S, Calvet X, Gabriel R, Carballo F, et al. Meta-analysis: proton pump inhibitors vs. H2-receptor antagonists—their efficacy with antibiotics in Helicobacter pylori eradication. Aliment Pharmacol Ther. 2003;18:757–66.

    Article  CAS  PubMed  Google Scholar 

  5. Welage LS. Overview of pharmacologic agents for acid suppression in critically ill patients. Am J Health Syst Pharm. 2005;62:S4–10.

    CAS  PubMed  Google Scholar 

  6. Zed PJ, Loewen PS, Slavik RS, Marra CA. Meta-analysis of proton pump inhibitors in treatment of bleeding peptic ulcers. Ann Pharmacother. 2001;35:1528–34.

    Article  CAS  PubMed  Google Scholar 

  7. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor therapy for peptic ulcer bleeding: cochrane collaboration meta-analysis of randomized controlled trials. Mayo Clin Proc. 2007;82:286–96.

    CAS  PubMed  Google Scholar 

  8. Brandstrom A, Lindberg P, Bergman N-A, Alminger T, Ankner K, et al. Chemical reactions of omeprazole and omeprazole analogues. I. A survey of the chemical transformations of omeprazole and its analogues. Acta Chem Scand. 1989;B43:536–48.

    Article  Google Scholar 

  9. Mattsson JP, Vaananen K, Wallmark B, Lorentzon P. Omeprazole and bafilomycin, two proton pump inhibitors: differentiation of their effects on gastric, kidney and bone H(+)-translocating ATPases. Biochim Biophys Acta. 1991;1065:261–8.

    Article  CAS  PubMed  Google Scholar 

  10. Mizunashi K, Furukawa Y, Katano K, Abe K. Effect of omeprazole, an inhibitor of H+, K(+)-ATPase, on bone resorption in humans. Calcif Tissue Int. 1993;53:21–5.

    Article  CAS  PubMed  Google Scholar 

  11. Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int. 2006;79:76–83.

    Article  CAS  PubMed  Google Scholar 

  12. Burdan F, Siezieniewska Z, Maciejewski R, Madej B, Radzikowska E, et al. Hepatic lysosomal enzymes activity and liver morphology after short-time omeprazole administration. Exp Toxicol Pathol. 2002;53:453–9.

    Article  CAS  PubMed  Google Scholar 

  13. Fujisaki H, Oketani K, Nagakawa J, Takenaka O, Yamanishi Y. Effects of rabeprazole, a gastric proton pump inhibitor, on biliary and hepatic lysosomal enzymes in rats. Jpn J Pharmacol. 1998;76:279–88.

    Article  CAS  PubMed  Google Scholar 

  14. Grinpukel S, Sewell R, Yeomans N, Mihaly G, Smallwood R. Lack of effect of omeprazole, a potent inhibitor of gastric (H+ + K+) ATPase, on hepatic lysosomal integrity and enzyme activity. J Pharm Pharmacol. 1986;38:158–60.

    Article  CAS  PubMed  Google Scholar 

  15. Trinidad JC, Thalhammer A, Specht CG, Lynn AJ, Baker PR, et al. Quantitative analysis of synaptic phosphorylation and protein expression. Mol Cell Proteomics. 2008;7:684–96.

    Article  CAS  PubMed  Google Scholar 

  16. Kilinc MO, Aulakh KS, Nair RE, Jones SA, Alard P, et al. Reversing tumor immune suppression with intratumoral IL-12: activation of tumor-associated T effector/memory cells, induction of T suppressor apoptosis, and infiltration of CD8+ T effectors. J Immunol. 2006;177:6962–73.

    CAS  PubMed  Google Scholar 

  17. Hill HC, Conway TF Jr, Sabel MS, Jong YS, Mathiowitz E, et al. Cancer immunotherapy with interleukin 12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres: coinduction of innate and adaptive antitumor immunity and cure of disseminated disease. Cancer Res. 2002;62:7254–63.

    CAS  PubMed  Google Scholar 

  18. Terpstra AH. Differences between humans and mice in efficacy of the body fat lowering effect of conjugated linoleic acid: role of metabolic rate. J Nutr. 2001;131:2067–8.

    CAS  PubMed  Google Scholar 

  19. Jalving M, Koornstra JJ, Wesseling J, Boezen HM, De Jong S, et al. Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther. 2006;24:1341–8.

    Google Scholar 

  20. Choudhry U, Boyce HW Jr, Coppola D. Proton pump inhibitor-associated gastric polyps: a retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics. Am J Clin Pathol. 1998;110:615–21.

    CAS  PubMed  Google Scholar 

  21. Cats A, Schenk BE, Bloemena E, Roosedaal R, Lindeman J, et al. Parietal cell protrusions and fundic gland cysts during omeprazole maintenance treatment. Hum Pathol. 2000;31:684–90.

    Article  CAS  PubMed  Google Scholar 

  22. Ekman L, Hansson E, Havu N, Carlsson E, Lundberg C. Toxicological studies on omeprazole. Scand J Gastroenterol Suppl. 1985;108:53–69.

    CAS  PubMed  Google Scholar 

  23. Haga Y, Nakatsura T, Shibata Y, Sameshima H, Nakamura Y, et al. Human gastric carcinoid detected during long-term antiulcer therapy of H2 receptor antagonist and proton pump inhibitor. Dig Dis Sci. 1998;43:253–7.

    Article  CAS  PubMed  Google Scholar 

  24. Dawson R, Manson JM. Omeprazole in oesophageal reflux disease. Lancet. 2000;356:1770–1.

    Article  CAS  PubMed  Google Scholar 

  25. Hodgson N, Koniaris LG, Livingstone AS, Franceschi D. Gastric carcinoids: a temporal increase with proton pump introduction. Surg Endosc. 2005;19:1610–2.

    Article  CAS  PubMed  Google Scholar 

  26. Waldum HL, Gustafsson B, Fossmark R, Qvigstad G. Antiulcer drugs and gastric cancer. Dig Dis Sci. 2005;50(Suppl 1):S39–44.

    Article  CAS  PubMed  Google Scholar 

  27. Jianu CS, Lange OJ, Viset T, Qvigstad G, Martinsen TC, et al. Gastric neuroendocrine carcinoma after long-term use of proton pump inhibitor. Scand J Gastroenterol. 2012;47:64–7.

    Article  CAS  PubMed  Google Scholar 

  28. Poulsen AH, Christensen S, McLaughlin JK, Thomsen RW, Sorensen HT, et al. Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. Br J Cancer. 2009;100:1503–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Hagiwara T, Mukaisho K, Nakayama T, Sugihara H, Hattori T. Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori. Gut. 2011;60:624–30.

    Article  CAS  PubMed  Google Scholar 

  30. Carter DC. Cancer after peptic ulcer surgery. Gut. 1987;28:921–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Caygill CP, Hill MJ, Kirkham JS, Northfield TC. Mortality from gastric cancer following gastric surgery for peptic ulcer. Lancet. 1986;1:929–31.

    Article  CAS  PubMed  Google Scholar 

  32. Freston JW. Clinical significance of hypergastrinaemia: relevance to gastrin monitoring during omeprazole therapy. Digestion. 1992;51(Suppl 1):102–14.

    Article  PubMed  Google Scholar 

  33. Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-suppressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology. 1997;8:571–4.

    Article  CAS  PubMed  Google Scholar 

  34. Doorduyn Y, Van Pelt W, Siezen CL, Van Der Horst F, Van Duynhoven YT, et al. Novel insight in the association between salmonellosis or campylobacteriosis and chronic illness, and the role of host genetics in susceptibility to these diseases. Epidemiol Infect. 2008;136:1225–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Neal KR, Briji SO, Slack RC, Hawkey CJ, Logan RF. Recent treatment with H2 antagonists and antibiotics and gastric surgery as risk factors for Salmonella infection. BMJ. 1994;308:176.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Garcia Rodriguez LA, Ruigomez A, Panes J. Use of acid-suppressing drugs and the risk of bacterial gastroenteritis. Clin Gastroenterol Hepatol. 2007;5:1418–23.

    Article  PubMed  Google Scholar 

  37. Doorduyn Y, Van Den Brandhof WE, Van Duynhoven YT, Wannet WJ, Van Pelt W. Risk factors for Salmonella Enteritidis and Typhimurium (DT104 and non-DT104) infections in The Netherlands: predominant roles for raw eggs in Enteritidis and sandboxes in Typhimurium infections. Epidemiol Infect. 2006;134:617–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Neal KR, Scott HM, Slack RC, Logan RF. Omeprazole as a risk factor for campylobacter gastroenteritis: case–control study. BMJ. 1996;312:414–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007;102:2047–56; quiz 2057.

    Google Scholar 

  40. Dial MS. Proton pump inhibitor use and enteric infections. Am J Gastroenterol. 2009;104(Suppl 2):S10–6.

    Article  CAS  PubMed  Google Scholar 

  41. Howell MD, Novack V, Grgurich P, Soulliard D, Novack L, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170:784–90.

    Article  PubMed  Google Scholar 

  42. Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010;170:772–8.

    Article  PubMed  Google Scholar 

  43. Sheen E, Triadafilopoulos G. Adverse effects of long-term proton pump inhibitor therapy. Dig Dis Sci. 2011;56:931–50.

    Article  CAS  PubMed  Google Scholar 

  44. Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet. 1996;31:9–28.

    Article  CAS  PubMed  Google Scholar 

  45. Andersson T, Olsson R, Regardh CG, Skanberg I. Pharmacokinetics of [14C]omeprazole in patients with liver cirrhosis. Clin Pharmacokinet. 1993;24:71–8.

    Article  CAS  PubMed  Google Scholar 

  46. Slattery E, Theyventhiran R, Cullen G, Kennedy F, Ridge C, et al. Intravenous proton pump inhibitor use in hospital practice. Eur J Gastroenterol Hepatol. 2007;19:461–4.

    Article  CAS  PubMed  Google Scholar 

  47. Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ. 2008;336:2–3.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Choudhry MN, Soran H, Ziglam HM. Overuse and inappropriate prescribing of proton pump inhibitors in patients with Clostridium difficile-associated disease. QJM. 2008;101:445–8.

    Article  CAS  PubMed  Google Scholar 

  49. van Boxel OS, Hagenaars MP, Smout AJ, Siersema PD. Socio-demographic factors influence chronic proton pump inhibitor use by a large population in the Netherlands. Aliment Pharmacol Ther. 2009;29:571–9.

    Article  PubMed  Google Scholar 

  50. Gawron AJ, Rothe J, Fought AJ, Fareeduddin A, Toto E, et al. Many patients continue using proton pump inhibitors after negative results from tests for reflux disease. Clin Gastroenterol Hepatol. 2012;10:620–5.

    Article  PubMed Central  PubMed  Google Scholar 

  51. Moore DJ, Tao BS, Lines DR, Hirte C, Heddle ML, et al. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr. 2003;143:219–23.

    Article  CAS  PubMed  Google Scholar 

  52. Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr. 2009;154(514–520):e514.

    Article  Google Scholar 

  53. Hassall E. Over-prescription of acid-suppressing medications in infants: how it came about, why it’s wrong, and what to do about it. J Pediatr. 2012;160:193–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a departmental start-up fund (to L.Z.). Mass spectrometry analysis was provided by the UCSF Mass Spectrometry Facility (A.L. Burlingame, Director) supported by the Biomedical Research Technology Program of the National Center for Research Resources, NIH NCRR RR001614 and NIH NCRR RR019934.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Women and Children’s Hospital of Buffalo and Department of Pediatrics, SUNY at Buffalo, Buffalo, NY, 14222, USA

    Wensheng Liu, Susan S. Baker, Robert D. Baker & Lixin Zhu

  2. Department of Pharmaceutical Chemistry, Mass Spectrometry Facility, University of California, San Francisco, CA, 94143, USA

    Jonathan Trinidad & Alma L. Burlingame

  3. Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA

    John G. Forte

  4. Department of Microbiology and Immunology, SUNY at Buffalo, Buffalo, NY, 14222, USA

    Lauren P. Virtuoso & Nejat K. Egilmez

  5. DDNC, Department of Pediatrics, SUNY at Buffalo, 3435 Main Street, 422 BRB, Buffalo, NY, 14222, USA

    Lixin Zhu

Authors
  1. Wensheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan S. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan Trinidad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alma L. Burlingame
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert D. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John G. Forte
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lauren P. Virtuoso
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nejat K. Egilmez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lixin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lixin Zhu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, W., Baker, S.S., Trinidad, J. et al. Inhibition of lysosomal enzyme activities by proton pump inhibitors. J Gastroenterol 48, 1343–1352 (2013). https://doi.org/10.1007/s00535-013-0774-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-013-0774-5

Keywords

Search

Navigation