Effects of Sulphasalazine and Its Metabolites on Prostaglandin Synthesis, Inactivation and Actions on Smooth Muscle

Abstract

6 Prostaglandin biosynthesis from arachidonic acid was measured in microsomal preparations from four sources by bioassay and radiochemical methods. Indomethacin was a potent inhibitor (ID50 0.8 to 4.1 pM) but sulphasalazine and its methyl analogue were very weak inhibitors (ID50 1500 to > 5000 gM), 5-aminosalicylic acid was weaker still and sulphapyridine inactive. 7 Sulphasalazine at 50 gM did not affect the actions of prostaglandins on five smooth muscle preparations; at 500 gM 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. IntroductdonWe have shown recently that sulphasalazine is a to inhibit prostaglandin breakdown were achieved in potent inhibitor of prostaglandin inactivation in cellcolon (but not in lung or kidney) after treating rats free homogenates but is only a feeble inhibitor of chronically with oral doses comparable to those used prostaglandin biosynthesis from arachidonic acid clinically in the treatment of ulcerative colitis (Moore,

EFFECT OF SULPHASALAZINE ON PULMONARY INACTIVATION OF PROSTAGLANDIN F2α IN THE PIG

“…Sulphasalazine inhibited the metabolism of PGF2., in 100,000 g supernatant fractions from piglet lung, as might be expected from its known inhibition of PGDH in several other species and tissues (Hoult & Moore, 1980 (1979) showed that porcine lung slices metabolized PGF2. and PGA, and there has been a brief report describing pulmonary metabolism of infused PGF2 by the adult pig in vivo (Davis, Fleet, Harrison & MauleWalker, 1980), but we are not aware of previous studies of prostaglandin inactivation in the porcine isolated perfused lung.…”

“…Inhibition of prostaglandin uptake has been directly shown for bromcresol green, by demonstrating that it inhibits inactivation in the perfused lung at concentrations that have no effect on PGDH (Bito & Baroody, 1975). Several other drugs including probenecid, frusemide, diphloretin phosphate and sulphasalazine reduce prostaglandin inactivation in the lung but also inhibit PGDH (Crutchley & Piper, 1974;Bito & Baroody, 1975;Eling et al, 1977;Bakhle, 1979;Hoult & Moore, 1980). Therefore it is uncertain .whether the action of these drugs in the perfused lung is due primarily to effects on PGDH or whether they may inhibit prostaglandin transport.…”

Nuclear factor κB is a key transcription factor in the duodenal contractility alterations induced by lipopolysaccharide

“…In fact, it has been reported that sulfasalazine partly inhibited the responses evoked by prostaglandin E 2 or prostaglandin F 2α in the smooth muscle from guineapig ileum, rat colon and rabbit jejunum (Hoult & Moore, 1980). However, the reduced contraction of circular smooth muscle isolated from rat colon with trinitrobenzene sulfonic acid (TNBS)-induced colitis was partly recovered by pretreatment with PDTC and sulfasalazine (Kinoshita et al 2003).…”

ULCERATIVE COLITIS: EFFECT OF SULPHASALAZINE, ITS METABOLITES AND INDOMETHACIN ON THE ABILITY OF HUMAN COLONIC MUCOSA TO METABOLIZE PROSTAGLANDINS in vitro

“…Prostaglandins have a cytoprotective effect and are able to prevent intestinal damage by a variety of noxious stimuli (Miller & Jacobson, 1979;Robert, 1980); moreover, prostaglandins can inhibit some aspects of the inflammatory process (Bonta & Parnham, 1978). Furthermore, Hoult & Moore (1980) have shown that sulphasalazine can inhibit prostaglandin metabolism in a variety of laboratory animal tissues, suggesting the alternative hypothesis that enhanced mucosal prostaglandins may not adversely affect the disease state, but may be beneficial. This paper describes the results of a study on the prostaglandin metabolic capacity of normal and ulcerative colonic mucosa and the effect of sulphasalazine, 5-ASA and indomethacin on prostag-landin metabolism by the human colonic mucosa.…”