Constitutive cyclooxygenase-2 expression in healthy human and rabbit gastric mucosa.
Selective cyclooxygenase (COX)-2 inhibitors are expected to cause fewer gastric side effects because of sparing of COX-1-dependent prostaglandin (PG) synthesis in the gastric mucosa. However, the possible contribution of COX-2 to overall gastric PG biosynthesis is not known. This study demonstrates constitutive expression of COX-2 mRNA and protein in apparently healthy human and rabbit gastric mucosa. This basal expression of COX-2 protein in human gastric mucosa was increased by lipopolysaccharide and phorbol ester, indicating its up-regulation in response to appropriate stimuli. The functional significance of COX-2-dependent PG formation was studied in terms of PGE2 generation in the rabbit mucosa and its inhibition by the COX-2-selective inhibitor flosulide. There was concentration-dependent (IC50 = 107 +/- 55 nM) and ultimately complete inhibition of PGE2 generation by flosulide. In addition, gastric mucosa generated 15-hydroxyeicosatetraenoic acid upon treatment with acetylsalicylic acid. The data suggest an important role for COX-2-dependent PG production in apparently healthy gastric mucosa and raise the issue of whether selective COX-2 inhibitors might also interfere with physiological PG formation and actions in the stomach.
Zimmermann
K C
KC
Institut für Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
Sarbia
M
M
Schrör
K
K
Weber
A A
AA
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007189:Indans / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D011817:Rabbits
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D007189:Indans; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C059178:flosulide; D015232:Dinoprostone; D001241:Aspirin