TY - JOUR
T1 - Inhibition of platelet thromboxane synthetase by sulfasalazine
AU - Stenson, William F.
AU - Lobos, Elizabeth
N1 - Funding Information:
Acknowledgements-W. F. S. is the recipient of clinical investigatora ward l-K08-AM00871-01f rom the National Instituteo f Arthritis, Metabolisma nd DigestiveD iseases. The authorst hank CatherineC amp for help in preparing the manuscripta nd Andrea Wychea nd Phillip Needleman for helpful discussions.
PY - 1983/7/15
Y1 - 1983/7/15
N2 - Sulfasalazine is a potent antiinflammatory drug used in the treatment of ulcerative colitis. The mechanism of action of sulfasalazine is unknown but a recent study [W.F. Stenson and E. Lobos, J. clin. Invest. bd69, 494 (1982)] demonstrated that sulfasalazine, at therapeutic concentrations, blocks human neutrophil lipoxygenase, suggesting that its antiinflammatory effects may be mediated in part by the inhibition of the synthesis of the chemotactic lipids 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB4). In the present study the effect of sulfasalazine on metabolism of exogenous arachidonic acid by human platelets was investigated. Sulfasalazine inhibited platelet thromboxane synthetase (ic50 = 0.9 mM) and partially inhibited cyclooxygenase. A methylated analog of sulfasalazine also inhibited thromboxane synthetase (ic50 = 0.3 mM) and partially inhibited cyclooxygenase. Neither of the cleavage products of sulfasalazine (5-aminosalicylate and sulfapyridine) inhibited thromboxane synthetase although 5-aminosalicylate blocked cyclooxygenase (ic50 = 5 mM). Neither sulfasalazine nor the methylated analog nor the cleavage products inhibited platelet lipoxygenase. This is in contrast to the inhibitory effects of sulfasalazine on neutrophil 5-lipoxygenase. The concentration of sulfasalazine in the colons of treated patients is several-fold greater than the ic50 for thromboxane synthetase.
AB - Sulfasalazine is a potent antiinflammatory drug used in the treatment of ulcerative colitis. The mechanism of action of sulfasalazine is unknown but a recent study [W.F. Stenson and E. Lobos, J. clin. Invest. bd69, 494 (1982)] demonstrated that sulfasalazine, at therapeutic concentrations, blocks human neutrophil lipoxygenase, suggesting that its antiinflammatory effects may be mediated in part by the inhibition of the synthesis of the chemotactic lipids 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB4). In the present study the effect of sulfasalazine on metabolism of exogenous arachidonic acid by human platelets was investigated. Sulfasalazine inhibited platelet thromboxane synthetase (ic50 = 0.9 mM) and partially inhibited cyclooxygenase. A methylated analog of sulfasalazine also inhibited thromboxane synthetase (ic50 = 0.3 mM) and partially inhibited cyclooxygenase. Neither of the cleavage products of sulfasalazine (5-aminosalicylate and sulfapyridine) inhibited thromboxane synthetase although 5-aminosalicylate blocked cyclooxygenase (ic50 = 5 mM). Neither sulfasalazine nor the methylated analog nor the cleavage products inhibited platelet lipoxygenase. This is in contrast to the inhibitory effects of sulfasalazine on neutrophil 5-lipoxygenase. The concentration of sulfasalazine in the colons of treated patients is several-fold greater than the ic50 for thromboxane synthetase.
UR - http://www.scopus.com/inward/record.url?scp=0020594269&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(83)90227-7
DO - 10.1016/0006-2952(83)90227-7
M3 - Article
C2 - 6135423
AN - SCOPUS:0020594269
SN - 0006-2952
VL - 32
SP - 2205
EP - 2209
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 14
ER -