The COX-2 inhibitor nimesulide suppresses superoxide and 8-hydroxy-deoxyguanosine formation, and stimulates apoptosis in mucosa during early colonic inflammation in rats.
As we have shown previously [Tardieu,D., Jaeg,J.P., Cadet,J., Embvani,E., Corpet,D.E. and Petit,C. (1998) Cancer Lett, 134, 1-5], a 48-h treatment of 6% dextran sodium sulphate (DSS) in drinking water led to a reproducible 2-fold increase of the mutagenic oxidative lesion 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) in colonic mucosa DNA of rats in vivo. The aim of this study was to test the effect of nimesulide, a preferential COX-2 inhibitor, on the DSS-induced 8-oxodGuo increase. We show that nimesulide when administered orally, simultaneously with DSS at 5 mg/kg/day, not only totally prevents 8-oxodGuo formation but also suppresses the 5-fold increase of superoxide induced by DSS in the colonic mucosa. This was measured by in vivo formazan blue precipitation (P < 0.01 in the Wilcoxon test). Moreover, nimesulide enhances apoptosis by approximately 30% as compared with the already high level induced by DSS treatment (P < 0.01). It is suggested that the significant increase in mutagenic oxidative DNA damage, produced by mild acute colonic inflammation, could be important in the initiation of colon cancer in both animals and man. These effects may explain at least partly the well-documented protective action towards colon cancer by preferential COX-2 inhibitors, either xenobiotics such as nimesulide or natural nutrients.
Tardieu
D
D
Laboratoire associé INRA, 'Sécurité et hygiène des aliments', Ecole Nationale Vétérinaire, 23 chemin des Capelles, F-31076 Toulouse Cedex 3, France.
Jaeg
J P
JP
Deloly
A
A
Corpet
D E
DE
Cadet
J
J
Petit
C R
CR
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003092:Colitis / Q000201:enzymology / Q000473:pathology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000494:pharmacology*; D013481:Superoxides / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D013449:Sulfonamides; D013481:Superoxides; D000080242:8-Hydroxy-2'-Deoxyguanosine; D009195:Peroxidase; D003849:Deoxyguanosine; C012655:nimesulide