Indomethacin inactivates gastric peroxidase to induce reactive-oxygen-mediated gastric mucosal injury and curcumin protects it by preventing peroxidase inactivation and scavenging reactive oxygen.
We have investigated the mechanism of indomethacin-induced gastric ulcer caused by reactive oxygen species (ROS) and the gastroprotective effect of curcumin thereon. Curcumin dose-dependently blocks indomethacin-induced gastric lesions, showing 82% protection at 25 mg/kg. Indomethacin-induced oxidative damage by ROS as shown by increased lipid peroxidation and thiol depletion is almost completely blocked by curcumin. Indomethacin causes nearly fivefold increase in hydroxyl radical (()OH) and significant inactivation of gastric mucosal peroxidase to elevate endogenous H(2)O(2) and H(2)O(2)-derived ()OH, which is prevented by curcumin. In vitro studies indicate that indomethacin inactivates peroxidase irreversibly only in presence of H(2)O(2) by acting as a suicidal substrate. 5,5-Dimethyl-pyrroline-N-oxide (DMPO) protects the peroxidase, indicating involvement of indomethacin radical in the inactivation. Indomethacin radical was also detected in the peroxidase-indomethacin-H(2)O(2) system as DMPO adduct (a(N) = 15 G, a(beta)(H) = 16 G) by electron spin resonance spectroscopy. Curcumin protects the peroxidase in a concentration-dependent manner and consumes H(2)O(2) for its oxidation as a suitable substrate of the peroxidase, thereby blocking indomethacin oxidation. Curcumin can also scavenge ()OH in vitro. We suggest that curcumin protects gastric damage by efficient removal of H(2)O(2) and H(2)O(2) -derived ()OH by preventing peroxidase inactivation by indomethacin.
Chattopadhyay
Ishita
I
Department of Physiology, Indian Institute of Chemical Biology, Kolkata, India.
Bandyopadhyay
Uday
U
Biswas
Kaushik
K
Maity
Pallab
P
Banerjee
Ranajit K
RK
D000143:Acids / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology* / Q000293:injuries / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction / Q000187:drug effects; D010544:Peroxidases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D013379:Substrate Specificity
D000143:Acids; D015415:Biomarkers; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D010544:Peroxidases; D003474:Curcumin; D007213:Indomethacin