Effects of sulfasalazine and a sulfasalazine analogue on the formation of lipoxygenase and cyclooxygenase products.
A sulfasalazine analogue, 5'-(2,4-dichlorobenzoyl)2'-hydroxyphenylacetic acid (CL 42A), potently inhibited the formation of 5-lipoxygenase products (leukotrienes B4 and C4 and 5-hydroxyeicosatetraenoic acid) by human leukocytes. Half-maximal inhibition of leukotriene production was obtained with 5 and 10 microM CL 42A after stimulation with serum-treated zymosan or ionophore A23187, respectively. CL 42A was equipotent to nordihydroguaiaretic acid and about 50 times more potent than sulfasalazine and benoxaprofen in studies on the inhibition of LTB4 formation in leukocyte suspensions stimulated with serum-treated zymosan. Furthermore, CL 42A had no inhibitory effect on the production of 15-hydroxyeicosatetraenoic acid after incubation of human leukocytes with ionophore A23187 in the presence of exogenous arachidonic acid. Sulfasalazine inhibited the synthesis of 5-lipoxygenase products (5-hydroxyeicosatetraenoic acid and leukotriene B4: IC50 250 microM, leukotriene C4: IC50 100 microM) in a concentration-dependent manner but had no effect on 15-hydroxyeicosatetraenoic acid formation. The metabolites of sulfasalazine, sulfapyridine and 5-aminosalicylic acid, and the isomer, 4-aminosalicylic acid, were all less potent than sulfasalazine as inhibitors of leukotriene formation. Both CL 42A (IC50 20 microM) and sulfasalazine (IC50 500 microM) inhibited the synthesis of thromboxane B2 and hydroxyheptadecatrienoic acid in human platelet suspensions after arachidonic acid stimulation. However, while CL 42A inhibited cyclooxygenase, the inhibitory effect of sulfasalazine was exerted mainly on thromboxane synthase. The platelet formation of 12-hydroxyeicosatetraenoic acid was not inhibited by CL 42A whereas sulfasalazine had a weak inhibitory effect.
Tornhamre
S
S
Department of Physiological Chemistry, Karolinska Institutet, Stockholm, Sweden.
Edenius
C
C
Smedegård
G
G
Sjöquist
B
B
Lindgren
J A
JA
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D010131:Aminosalicylic Acid / Q000494:pharmacology; D000636:Aminosalicylic Acids / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology; D007975:Leukotriene B4 / Q000096:biosynthesis; D008084:Lipoxygenase / Q000378:metabolism*; D019804:Mesalamine; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013427:Sulfapyridine / Q000494:pharmacology; D012460:Sulfasalazine / Q000031:analogs & derivatives / Q000494:pharmacology*; D015054:Zymosan / Q000494:pharmacology
D000636:Aminosalicylic Acids; D001095:Arachidonic Acids; D006893:Hydroxyeicosatetraenoic Acids; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; D012460:Sulfasalazine; D019804:Mesalamine; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D010131:Aminosalicylic Acid; D015054:Zymosan; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D013427:Sulfapyridine