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Journal of Gastroenterology

, Volume 48, Issue 12, pp 1343–1352 | Cite as

Inhibition of lysosomal enzyme activities by proton pump inhibitors

  • Wensheng Liu
  • Susan S. Baker
  • Jonathan Trinidad
  • Alma L. Burlingame
  • Robert D. Baker
  • John G. Forte
  • Lauren P. Virtuoso
  • Nejat K. Egilmez
  • Lixin ZhuEmail author
Original Article—Alimentary Tract

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.

Keywords

Omeprazole Lansoprazole Pantoprazole 

Abbreviations

AP

Acid phosphatase

CID

Collision-induced dissociation

GERD

Gastroesophageal reflux disease

MPO

Myeloperoxidase

NAG

β-N-acetylglucosaminidase

PPIs

Proton pump inhibitors

Notes

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.

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Copyright information

© Springer Japan 2013

Authors and Affiliations

  • Wensheng Liu
    • 1
  • Susan S. Baker
    • 1
  • Jonathan Trinidad
    • 2
  • Alma L. Burlingame
    • 2
  • Robert D. Baker
    • 1
  • John G. Forte
    • 3
  • Lauren P. Virtuoso
    • 4
  • Nejat K. Egilmez
    • 4
  • Lixin Zhu
    • 1
    • 5
    Email author
  1. 1.Women and Children’s Hospital of Buffalo and Department of PediatricsSUNY at BuffaloBuffaloUSA
  2. 2.Department of Pharmaceutical Chemistry, Mass Spectrometry FacilityUniversity of CaliforniaSan FranciscoUSA
  3. 3.Department of Molecular and Cell BiologyUniversity of CaliforniaBerkeleyUSA
  4. 4.Department of Microbiology and ImmunologySUNY at BuffaloBuffaloUSA
  5. 5.DDNC, Department of PediatricsSUNY at BuffaloBuffaloUSA

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