Protection by polaprezinc, an anti-ulcer drug, against indomethacin-induced apoptosis in rat gastric mucosal cells.
Polaprezinc [N-(3-aminopropionyl)-L-histidinato zinc] (PZ), an anti-ulcer drug, is a chelate compound consisting of zinc and L-carnosine. PZ has been shown to prevent gastric mucosal injury. In the present study, we investigated the inhibitory effect of PZ on indomethacin (IND)-induced apoptosis in a rat gastric mucosal cell line, RGM1. Pretreatment with PZ suppressed caspase-3 activation and subsequent apoptosis in the cells exposed to 500 microM IND in a dose-dependent manner, and 50 microM PZ exhibited the maximum inhibitory effect. Among PZ subcomponents, zinc but not L-carnosine played a pivotal role in this antiapoptotic function. PZ did not affect mitochondrial cytochrome c release upstream of caspase-3 activation in the IND-induced apoptotic signal pathway. Treatment with 500 microM IND evidently produced reactive oxygen species (ROS) in RGM1 cells. However, PZ did not scavenge ROS in IND-treated cells. Moreover, N-acetylL-cysteine, a potent antioxidant, inhibited ROS generation but did not suppress apoptosis in RGM1 cells exposed to IND. These observations demonstrate a novel pharmacological action of PZ; i.e., that PZ, and in particular its zinc subcomponent, inhibits apoptosis via inhibition of caspase-3 activation but not antioxidant activity.
Fuji
Y
Y
Department of Biochemistry, Faculty of Medicine, Tottori University, Yonago, Japan.
Matsura
T
T
Kai
M
M
Kawasaki
H
H
Yamada
K
K
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D017209:Apoptosis; D002336:Carnosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects*; D007213:Indomethacin; D009942:Organometallic Compounds / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D015032:Zinc / Q000378:metabolism; D017967:Zinc Compounds; D019287:Zinc Sulfate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D003574:Cytochrome c Group; D009942:Organometallic Compounds; D020011:Protective Agents; D017382:Reactive Oxygen Species; D017967:Zinc Compounds; C061957:polaprezinc; D019287:Zinc Sulfate; D002336:Carnosine; D010447:Peptide Hydrolases; C108711:DEVDase; D015032:Zinc; D000111:Acetylcysteine; D007213:Indomethacin