Effects of sulphasalazine and its metabolites on prostaglandin synthesis, inactivation and actions on smooth muscle.
1 We have investigated the effects of sulphasalazine and of its principal colonic metabolites (5-aminosalicylic acid and sulphapyridine) on prostaglandin inactivation, synthesis and actions on gastrointestinal smooth muscle.2 Sulphasalazine inhibits prostaglandin F(2alpha) breakdown in 100,000 g supernatants in all organs so far tested from 7 species with an ID(50) of approx. 50 muM; it has a selective action on prostaglandin 15-hydroxydehydrogenase and does not inhibit prostaglandin Delta-13 reductase, prostaglandin 9-hydroxydehydrogenase or ;enzyme X' at millimolar concentrations. Enzyme activities were measured radiochemically or by bioassay.3 Sulphapyridine and 5-aminosalicylic acid do not inhibit prostaglandin inactivation in vitro (4 species tested). A methyl analogue of sulphasalazine is a more potent inhibitor than the parent compound. Rabbit colon prostaglandin F(2alpha) metabolism in vitro was inhibited by the following drugs with ID(50) values (muM) of: diphloretin phosphate 20, sulphasalazine 50, indomethacin 220, frusemide 1000 and aspirin 10,000. A similar rank order of potencies was obtained with rabbit kidney.4 Sulphasalazine at 50 to 100 muM inhibited inactivation of prostaglandin E(2) in the perfused rat and guinea-pig lung by 3 to 40% (rat) and 32 to 100% (guinea-pig) when measured by superfusion cascade bioassay and of prostaglandin F(2alpha) by 43.6 +/- 6.5% in rat lung perfused with 50 muM sulphasalazine and assayed radiochemically.5 Prostaglandins E(1) and E(2) were 97.0 +/- 8.2% and 92.3 +/- 6.8% inactivated in the lungs after intravenous injection in the anaesthetized rat as measured by reference to their vasodepressor potencies when injected intra-arterially. Prostaglandin A(2) was not similarly inactivated. Pulmonary inactivation was prevented in the presence of an intravenous infusion of 16.3 mug kg(-1) min(-1) sulphasalazine and partially inhibited at a lower infusion rate.6 Prostaglandin biosynthesis from arachidonic acid was measured in microsomal preparations from four sources by bioassay and radiochemical methods. Indomethacin was a potent inhibitor (ID(50) 0.8 to 4.1 muM) but sulphasalazine and its methyl analogue were very weak inhibitors (ID(50) 1500 to > 5000 muM), 5-aminosalicylic acid was weaker still and sulphapyridine inactive.7 Sulphasalazine at 50 muM did not affect the actions of prostaglandins on five smooth muscle preparations; at 500 muM there was a rapidly reversible and probably non-specific antagonism of responses to low doses of prostaglandins.8 The specificity and selectivity of the interaction of sulphasalazine and its metabolites with the formation, breakdown and actions of prostaglandins are discussed.
D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D004064:Digestive System / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D011460:Prostaglandins F / Q000378:metabolism; D051381:Rats; D013427:Sulfapyridine / Q000494:pharmacology; D012460:Sulfasalazine / Q000494:pharmacology*
D000636:Aminosalicylic Acids; D001095:Arachidonic Acids; D011453:Prostaglandins; D011460:Prostaglandins F; D012460:Sulfasalazine; D013427:Sulfapyridine