Role of tumour necrosis factor-alpha and inducible nitric oxide synthase in the prevention of nitro-flurbiprofen small intestine toxicity.
The present study compares the intestinal toxicity of nitro-flurbiprofen and flurbiprofen in order to determine their differential properties on tumour necrosis factor-alpha production and inducible nitric oxide synthase induction. Rats received one s.c. injection of flurbiprofen, nitro-flurbiprofen at equimolar dose of solvent. Twenty-four hours later, the rats were sacrificed and small intestine tissue was taken up for macroscopical quantification of ulceration, ex vivo production of tumour necrosis factor-alpha and nitrites, and determination of tissue inducible nitric oxide synthase and myeloperoxidase activities. Anti-inflammatory activity was examined in the carrageenan-induced paw edema model. We demonstrated that flurbiprofen induced dose-dependently small intestine production of tumour necrosis factor-alpha, nitrites, myeloperoxidase and inducible nitric oxide synthase activities. On the other hand, nitro-flurbiprofen did neither induce tumour necrosis factor-alpha nor nitrite production. Concurrently, no small intestine ulceration was observed with nitro-flurbiprofen whereas flurbiprofen induced dose-dependent ulceration. Nitro-flurbiprofen is devoid of intestinal toxicity despite inhibiting cyclooxygenase activity. This is associated with the absence of tumour necrosis factor-alpha and inducible nitric oxide synthase induction in normal rats. Nitro-flurbiprofen is an anti-inflammatory drug with a much more favorable gastro-intestinal toxicity profile than flurbiprofen.
Bertrand
V
V
Service d'Hépato-gastro-entérologie, CNRS URA 1534, Hôpital Cochin et Université René Descartes, Paris, France.
Guimbaud
R
R
Sogni
P
P
Lamrani
A
A
Mauprivez
C
C
Giroud
J P
JP
Couturier
D
D
Chauvelot-Moachon
L
L
Chaussade
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000633:toxicity; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000502:physiology; D014456:Ulcer / Q000139:chemically induced / Q000517:prevention & control
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; C095631:nitroflurbiprofen; D005480:Flurbiprofen; D009195:Peroxidase; D019001:Nitric Oxide Synthase