Omeprazole attenuates oxygen-derived free radical production from human neutrophils.
Neutrophil-derived oxygen radicals have been implicated in the pathogenesis of gastrointestinal disorders such as acute gastric mucosal injury induced by ischemia-reperfusion or by nonsteroidal antiinflammatory drugs (NSAIDs). The objectives of the present in vitro and clinical study were to determine whether omeprazole inhibits the production of toxic oxidants from neutrophils and to evaluate whether this drug affects intralysosomal pH. The respiratory burst of human neutrophils were was measured by luminol-dependent chemiluminescence (ChL) assay. The lysosomal pH of neutrophil was assessed by the fluorescence intensity ratio of phagocytized FITC-dextran using a digital-fluorescence video microscope. In vitro studies revealed that omeprazole (1-100 microM) dose dependently inhibited the ChL value of purified neutrophils that were elicited by FMLP (f-methionyl-leucyl-phenylalanine) or opsonized zymosan. Lysosomal pH was also increased in a dose-dependent manner by pretreatment with omeprazole. Healthy volunteers administered omeprazole, 40 mg/d for 7 d, showed a significant reduction in ChL values in peripheral neutrophils. These results suggest that omeprazole can inhibit the production of toxic oxidants by activated neutrophils. The action of omeprazole may be associated with a malfunction of lysosomal oxidant-producing enzymes due to an elevated intralysosomal pH.
Department of Internal Medicine and Biochemistry, School of Medicine, Keio University, Tokyo, Japan.
M
M
Suzuki
M
M
Mori
S
S
Miura
M
M
Suematsu
D
D
Fukumura
H
H
Kimura
H
H
Ishii
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D005609:Free Radicals / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D009853:Omeprazole / Q000494:pharmacology*; D054328:Proton Pump Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005609:Free Radicals; D054328:Proton Pump Inhibitors; D017382:Reactive Oxygen Species; D009853:Omeprazole