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Vol. 300, Issue 3, 754-761, March 2002
Department of Pharmacology and Experimental Therapeutics, Kyoto
Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan
Nonsteroidal anti-inflammatory drugs (NSAIDs) induce gastrointestinal
ulceration as the adverse reaction. This effect of NSAIDs is
attributable to endogenous prostaglandin (PG) deficiency caused by
inhibition of cyclooxygenase (COX), yet the relation between COX
inhibition and the gastrointestinal ulcerogenic property of NSAIDs
remains controversial. Using selective COX inhibitors, we examined
whether inhibition of COX-1 or COX-2 alone is sufficient for induction
of intestinal damage in rats. Various COX inhibitors were administered
p.o. in rats, and the animals were killed 24 h later. Mucosal
PGE2 levels were determined by enzyme immunoassay, whereas
the gene expression of COX isozymes was examined by reverse transcription-polymerase chain reaction. Nonselective COX inhibitors such as indomethacin inhibited PGE2 production and caused
damage in the small intestine. Selective COX-2 inhibitors (rofecoxib or
celecoxib) had no effect on the generation of PG, resulting in no
damage. A selective COX-1 inhibitor (SC-560) did not cause damage,
despite reducing PGE2 content. However, the combined
administration of COX-1 and COX-2 inhibitors provoked intestinal damage
with an incidence of 100%. COX-2 was up-regulated in the small
intestine after administration of SC-560, and the PGE2
content was restored 6 h later, in a rofecoxib-dependent manner.
The intestinal lesions induced by SC-560 plus rofecoxib were
significantly prevented by later administration of 16,16-dimethyl
PGE2. These results suggest that the intestinal ulcerogenic
property of NSAID is not accounted for solely by inhibition of COX-1
and requires inhibition of COX-2 as well. The inhibition of COX-1
up-regulates COX-2 expression, and this may be a key to NSAID-induced
intestinal damage.
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