Up-regulation of cyclooxygenase-2 by inhibition of cyclooxygenase-1: a key to nonsteroidal anti-inflammatory drug-induced intestinal damage.
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.
Tanaka
Akiko
A
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
Hase
Shoko
S
Miyazawa
Tohru
T
Takeuchi
Koji
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D004751:Enteritis / Q000139:chemically induced* / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D007783:Lactones / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013450:Sulfones; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; C115461:SC 560; D013450:Sulfones; C116926:rofecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone