title: Inhibition of lysosomal enzyme activities by proton pump inhibitors.
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.
authors.affiliation: Women and Children's Hospital of Buffalo and Department of Pediatrics, SUNY at Buffalo, Buffalo, NY, 14222, USA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Liu
authors.forename: Susan S
authors.initials: SS
authors.lastname: Baker
authors.forename: Jonathan
authors.initials: J
authors.lastname: Trinidad
authors.forename: Alma L
authors.initials: AL
authors.lastname: Burlingame
authors.forename: Robert D
authors.initials: RD
authors.lastname: Baker
authors.forename: John G
authors.initials: JG
authors.lastname: Forte
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Virtuoso
authors.forename: Nejat K
authors.initials: NK
authors.lastname: Egilmez
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhu
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004798:Enzymes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007107:Immune System / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods; D064747:Lansoprazole / Q000008:administration & dosage / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009853:Omeprazole / Q000008:administration & dosage / Q000494:pharmacology; D000077402:Pantoprazole; D011355:Prodrugs; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000201:enzymology
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D004798:Enzymes; D011355:Prodrugs; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D000077402:Pantoprazole; D009853:Omeprazole