Prostaglandin 15-hydroxydehydrogenase Research Articles

Highly potent inhibition of prostaglandin 15-hydroxydehydrogenase in-vitro and of prostaglandin inactivation in perfused lung by the new azobenzene analogue, Ph CL 28A

The new azobenzene analogue Ph CL 28A (2-hydroxy-5-(3,5-dimethoxycarbonyl-benzoyl)-benzene acetic acid) potently inhibited prostaglandin 15-hydroxydehydrogenase (PGDH) in the nanomolar range in-vitro and inhibited prostaglandin inactivation in rat perfused lung at similar concentrations, and is the most potent PGDH inhibitor yet available. It was synthesized because electronegative substituents in the B ring of homosalazine enhance PGDH inhibitory potency. Ph CL 28A inhibited human placental PGDH non-competitively with regard both to substrate PGF2 alpha (Ki = 18.7 +/- 0.9 nM) and the NAD+ cofactor (Ki = 57.6 +/- 2.9 nM); inhibition was greatly reduced at pH greater than or equal to 8.0. Ph CL 28A hydrolyses spontaneously in alkali (t1/2 at pH 9.0 = 45 h) to the less active dicarboxylic acid (IC50 human placental PGDH 1.6 microM versus 0.028 microM for Ph CL 28A). The new analogue is 1000 X more active than the parent compound sulphasalazine from which it derives. The IC50 values for five azobenzene analogues in rat perfused lung (Ph CL 28A = 72 nM) correlated strongly with those obtained using purified PGDH (r = 0.99), suggesting that they inhibit pulmonary prostaglandin degradation at the enzyme step rather than at the hypothetical carrier. The new compound will be a useful probe for PGDH structure and function.

Decidual Activation: Abundance and Localization of Prostaglandin F 2α Receptor (FP) mRNA and Protein and Uterine Activation Proteins in Human Decidua at Preterm Birth and Term Birth

Objective To study how the decidua contributes to parturition, we examined prostaglandin F 2α concentrations as well as prostaglandin 15-hydroxy dehydrogenase, prostaglandin F 2α receptor, matrix metalloproteinases 2 and 9, oxytocin receptor, prostaglandin-H synthase-2, and the prostaglandin E 2 receptor expression in human decidua. Materials and methods Decidual samples were isolated from placentas collected from patients at preterm not in labor (PTNIL), preterm labor (PTL), term not in labor (TNIL), and term labor (TL). For immunohistochemistry, fresh membranes which included chorion, amnion and decidua from term patients were collected. Results Prostaglandin F 2α receptor mRNA was low in all preterm patients and then significantly increased towards term ( p = 0.049). Prostaglandin F 2α receptor protein was identified in the amnion epithelium and mesoderm, chorion trophoblasts and decidua by immunohistochemistry, and levels were highest at TNIL ( p = 0.007) as measured by western blot. Prostaglandin F 2α levels were higher at PTNIL than TNIL. Matrix metalloproteinases 2 and 9 protein and pro-enzyme activities were higher at TL than TNIL. There were no significant changes among the groups for any of the other factors measured. Conclusions These results suggest that the induction of Prostaglandin F 2α receptor at term may facilitate the decidua contribution to parturition, and its regulation and role should be examined further.

Prostaglandin E2 Alterations during Sepsis Are Partially Mediated by Endotoxin-Induced Inhibition of Prostaglandin 15-Hydroxydehydrogenase

Prostaglandin E2 (PGE2) is significantly elevated in the plasma of septic or injured patients and is thought to be a component of the resultant immune suppression associated with augmented rates of infection and mortality. Many studies have examined the effect of burn injury and sepsis on PGE2 synthesis. However, the effect of sepsis or burn injury on the expression of prostaglandin 15-hydroxydehydrogenase (PGDH), the key enzyme responsible for PGE2 degradation, has not been explored. The aim of this study was to examine the effect of endotoxin treatment and/or burn injury on the expression of PGDH. Male BDF1 mice were assigned to four groups (n = 4/group): sham, lipopolysaccharide (LPS) (2.5 mg/kg, Escherichia coli LPS, i.p.), burn (15% body surface area scald injury), and burn + LPS (15% body surface area + 2.5 mg/kg LPS, i.p.). Lung tissue was harvested at specific time points after treatment and subsequently was processed for total RNA and protein. Northern and Western blot analyses were used to examine differences in PGDH protein and mRNA expression. Total RNA was probed with the riboprobe for murine PGDH, and the 100,000 g protein fraction was immunoblotted using an rabbit antimurine PGDH antibody. PGDH was expressed in lung at t = 0 in both the saline and LPS-treated animals. A decrease in mRNA expression was initially observed at 2 hours after LPS treatment. The decrease was also significant (p < 0.05) at 3 hours after LPS and maximal decrease in mRNA and protein expression was observed at 6 hours. At 24 hours after LPS administration, the PGDH mRNA and protein expression was still significantly depressed to 49% of control expression. PGDH expression was similar and not statistically different in both burn and burn + LPS treatment at t = 0. At 2 hours after LPS, PGDH mRNA expression in the burn + LPS treatment group had significantly decreased to 47% in comparison with the burn alone group. Maximal decrease in PGDH mRNA and protein expression in lung from burn + LPS was observed at 6 hours after LPS treatment. This change represents a 73% decrease in mRNA in comparison with the time-matched burn control. At 24 hours after LPS administration, PGDH mRNA but not protein expression in the lung from burn + LPS treated mice was still significantly decreased. In summary, LPS treatment alters PGDH mRNA expression at the transcriptional and protein levels. Consequently, sepsis-induced increases in PGE2 levels may not be only due to increased PGE2 synthesis but also due to decreased PGDH expression and, hence, PGE2 degradation.

Prostaglandin E sub 2 Alterations During Sepsis are Partially Mediated by Endotoxin-induced Inhibition of Prostaglandin 15-Hydroxy Dehydrogenase (PGDH)

s Of Papers To Be Presented At The Joint Meeting Of The American Association For The Surgery Of Trauma (Fifty-Seventh Annual Meeting) And The Japanese Association For Acute Medicine; The Hilton Waikoloa Village, Waikoloa, Hawaii September 24-27, 1997

Purification of human placental prostaglandin 15-hydroxydehydrogenase

The NAD+-linked prostaglandin 15-hydroxydehydrogenase, which is responsible for the physiological inactivation of prostaglandins by catalysing the first step in the catabolism, was isolated and purified 995-fold from human placenta. The introduction of two new chromatographic steps in the purification procedure is responsible for an achieved specific activity of 1791 mU/mg. The molecular mass of the enzyme, as estimated by fast protein liquid chromatography, was 24 500 dalton. Sodium dodecyl sulphate discontinuous gel electrophoresis of the denatured enzyme revealed a molecular mass of 24 000 dalton. These data suggest that the enzyme consists of a single polypeptide chain.

Prostaglandin 15-hydroxydehydrogenase activity in human penile corpora cavernosa and its significance in prostaglandin-mediated penile erection.

Prostaglandins may be involved in human penile erection and erectile failure. To evaluate the possible role of prostaglandin metabolism in the penile tissue, the activity of nicotinamide adenine dinucleotide-dependent prostaglandin 15-hydroxydehydrogenase was assayed in the corpora cavernosa of the human penis. Km values (mean +/- SD) of the enzyme for PGE1, PGE2 and PGF2 alpha were 60.1 +/- 4.2, 17.7 +/- 1.5 and 16.1 +/- 1.2 microM respectively; Vmax values (mean +/- SD) were 0.219 +/- 0.062, 0.510 +/- 0.012 and 0.424 +/- 0.007 nmol/min/mg protein respectively. The implications of these findings in the erectile process are discussed.

Changes in vascular endothelium and its function in systemic arterial hypertension

The various functions of arterial endothelium may be altered during pulmonary and arterial hypertension. Changes in the endothelium (or function) associated with hypertension are described. In both acute and chronic hypertension, permeability of the endothelium is enhanced. During the acute phase of hypertension, hyperplasia (cell replication) of the endothelium occurs while cell hypertrophy (enlarged cell size) and an increase in homocellular tight junctions are associated with sustained elevations of blood pressure. Endothelium may contribute to the increase in smooth muscle mass or cell number reported with various models of hypertension. Increased endothelial uptake or metabolism of norepinephrine and serotonin occurs during hypertension. The biotransformation of adenine nucleotides and various peptides by the endothelium is not altered by hypertension. Synthesis of prostacyclin is enhanced in the spontaneously hypertensive and Goldblatt hypertensive rat. Metabolism of prostaglandin E 2, prostaglandin F 2α and prostacyclin by prostaglandin 15-hydroxydehydrogenase is impaired in the genetic models. Responses to endothelium-dependent vasodilators are impaired in acute and chronic models of hypertension. Production of relaxing factor by the endothelium is not inhibited, but rather the vascular smooth muscle fails to respond. Acute, severe hypertension potentiates the response to serotonin, presumably by attenuating the release or response to relaxing factor(s). In the aorta of the spontaneously hypertensive rat, the endothelium releases a constricting factor in response to acetylcholine. Pulmonary arterial endothelium (and other vessels) releases a vasoconstrictor that is blocked by inhibitors of cyclooxygenase. It is not clear whether this pressor factor is thromboxane A 2. Cultured endothelial cells release a polypeptide that contracts arteries; however, any relation to hypertension is not known.

Actions of flavonoids and the novel anti-inflammatory flavone, hypolaetin-8-glucoside, on prostaglandin biosynthesis and inactivation

The newly identified plant-derived flavone-glycoside hypolaetin-8-glucoside, which has anti-inflamatory and gastric ulcer protective properties, and its corresponding aglycone, hypolaetin, were tested for effects on prostaglandin biosynthesis and degradation. They were compared with four other flavonoids, viz. rutin and its corresponding aglycone, quercetin, and the aglycones isoscutellarein and kaempferol. Over the range 10–1000 μM the glycosides rutin and hypolaetin-8-glucoside stimulated prostaglandin formation by sheep seminal vesicle microsomes incubated with radiolabelled arachidonic acid; the other compounds were essentially inactive. Over 5–5000 μM rutin and hypolaetin-8-glucoside enhanced the release of prostacyclin (and other prostanoids) from fragments of rat caecum incubated in the absence of additional arachidonic acid; the four aglycones compoundsdid not stimulate prostacyclin release but some reduced it at 5000 μM. However, the glycosides did not affect the enzymatic inactivation of radiolabelled prostaglandin F 2α by semi-purified bovine lung prostaglandin 15-hydroxydehydrogenase (PGDH) or in 100,000 g supernatants prepared from homogenised rat stomach. Three of the four aglycones (quercetin, kaempferol, isoscutellarein, in descending order of potency) were inhibitory to PGDH with id 50 values in the range 130–2100 μM. The results show that the capacity of flavonoids to enhance prostaglandin formation is associated with the presence of glycosidic substitution, whereas PGDH inhibition requires its absence. The relevance of this biochemical profile of hypolaetin-8-glucoside to its anti-inflammatory gastroprotective effects in vivo is discussed.

Enzymatic inactivation of 6-keto-prostaglandin E 1 in vitro: Comparison with prostaglandin E 1

The inactivation of 6-keto PGE 1, a biologically active and stable metabolite of prostacyclin, was studied in 100,000 g cytosolic supernatants by bioassay on rat stomach strip (contraction) and human platelets (inhibition of ADP-induced aggregation). PGE 1 was used as a reference compound. Both PGs were inactivated in supernatants from colon, kidney and liver of rat, rabbit and guinea-pig. Inactivation was time- and NAD +-dependent and was generally greater for PGE 1 than 6-keto-PGE 1. The enzyme responsible for 6-keto-PGE 1 inactivation in cytosolic supernatants is distinct from prostaglandin 15-hydroxydehydrogenase and 9-keto reductase, is not inhibitable by sulphasalazine-like drugs and its activity is recoverable after precipitation by ammonium sulphate. We conclude that 6-keto-PGE 1 can be inactivated by enzymes with wide tissue distribution, but further studies are needed for identification of these novel enzymes and the products formed as well as to assess their significance in the intact animal.

ChemInform Abstract: SYNTHESIS OF 2‐(4‐AZULENYL)ETHANAMINE DERIVATIVES AS A NONBENZENOID ANALOG OF BIOGENIC AMINE

AbstractDurch Reaktion der Azulene (I), (VI) bzw. (X) mit den Ammoniumsalzen (III) bzw. (III), (XIII) und (XIV) werden nach entsprechender Aufarbeitung die violetten Derivate (IV) und (V) sowie (VII)‐(IX) bzw. die blauen Derivate (XI) und (XII) erhalten.

Inhibition of prostaglandin 15-hydroxydehydrogenase by sulphasalazine and a novel series of potent analogues

The ability of sulphasalazine, its colonic metabolites and various analogues to inhibit prostaglandin inactivation by two purified preparations of type INAD +-dependent prostaglandin 15-hydroxydehydrogenase or in various 100,000 g cytosolic supernatants was investigated using PGF 2a as substrate and radio-TLC. Bovine lung and human placental PGDH were inhibited in a dose-dependent and apparently non-competitive manner by sulphasalazine and most of the 26 salazine/sulphasalazine analogues tested, but the potencies of the analogues varied considerably. In a survey of structure-activity effects testing 30 drugs at a fixed dose (50 μM) in six test systems, it was established that only two aromatic rings are needed and that optimal PGDH inhibition requires -CH 2COOH and -OH at positions 1 and 2 in the salicyl C ring system. Homosalazine was thus established as the type compound of a novel series of powerful PGDH inhibitors. Electronegative substituents meta or para in ring B produce compounds with > 150 × inhibitory potency of sulphasalazine, and a significant linear corrlation ( r = 0.82, P < 0.002) was found between the inhibitory activity and the Hammett σ substituent Constant in this series of ten homosalazine analogues.

Synthesis of 2-(4-Azulenyl)ethanamine Derivatives as a Nonbenzenoid Analog of Biogenic Amine

Abstract 2-(4-Azulenyl)ethanamine derivatives, nonbenzenoid analogs of the biologically active amine, were synthesized by the action of methyleneammonium salts on sodium 4-methylazulenide, sodium 4,6,8-trimethylazulenide, and sodium guaiazulenide. These compounds, as well as their hydrochlorides, were characterized by UV, IR, 1H NMR, 13C NMR, and MS data. The reaction of sodium guaiazulenide and N-ethylidenemethylamine also yielded the corresponding 2-(4-azulenyl)ethanamine derivatives, but the low yield of the product showed that the electrophilicity of azomethine carbon atom to 4-methylene carbanion was insufficient. The enzyme activity for some of those products was investigated. Negligible effect was found on prostaglandin 15-hydroxydehydrogenase, and considerable inhibition to cyclic AMP-phosphodiesterase, in vitro.

Synthesis of 2-(1-Azulenyl)ethanamine Derivatives by Aminoethylation of Azulenes with Aziridines

Abstract Azulene analogs of biological active amines were synthesized. Reaction of azulene or guaiazulene with 1-butanoylaziridine or with 1-butanoyl-2-methylaziridine in the presence of Lewis acid catalyst formed the corresponding N-butanoyl-1-(1-azulenyl)-, N-butanoyl-2-(1-azulenyl)-, and N-butanoyl-2-(1-guaiazulenyl) derivatives of ethanamine, or 1-propanamine, or of 2-propanamine, respectively (5–9). Reaction of guaiazulene with 2-methyl-, or 1,1-dimethylaziridinium, or with 1,1,2,2-tetramethylaziridinium ions gave the corresponding 1-(1-guaiazulenyl)- and 2-(1-guaiazulenyl) derivatives of ethanamine, or 1-propanamine, or of 2-propanamine. 2-(1-Azulenyl)- and 2-(4,6,8-trimethyl-1-azulenyl) derivatives of ethanamine were also obtained by the action of 1,1-diethylaziridinium ion on azulene or on 4,6,8-trimethylazulene. Compounds 5, 6, and 9 were active in vitro in the inhibition of prostaglandin 15-hydroxydehydrogenase and of cyclic AMP-phosphodiesterase.

Effects on fertilization of rabbits of insemination with ejaculates treated with PG-dehydrogenase and antisera to PGE-2 and PGF-2 alpha.

PGE-2 and PGF-2 alpha in rabbit semen were selectively inactivated by incubation with antisera, or most of the seminal prostaglandins were transformed into biologically inactive 15-keto-prostaglandins by prostaglandin-15-hydroxydehydrogenase(PG-15-HDH). These treated ejaculates were vaginally inseminated. Compared to the controls (738 eggs of which 94% were fertilized) a dose-dependent reduction of the fertilization rate was observed with the anti-PGF-2 alpha-treated ejaculates. A non-uniformly, but statistically significantly reduced fertility was found in the other 2 treatment groups. After incubation with higher doses of PG-15-HDH, some fertilization was accomplished with ejaculates showing an extremely weak forward progression or immotile spermatozoa. An improvement in sperm motility, however, was observed in ejaculates treated with antiserum to PGF-2 alpha. Seminal prostaglandins may not exclusively affect sperm motility. The observed influences on the fertilization rate after treatment of spermatozoa with antisera to PGE-2 and PGF-2 alpha or PG-15-HDH suggest that these are local effects in the female genital tract.

6-Keto-prostaglandin E1: its formation by platelets from prostacyclin and resistance to pulmonary degradation.

6-Keto-prostaglandin E1 is a novel biologically active product of the metabolism of prostacyclin in liver and platelets. Further evidence for this bioconversion was obtained in stirred suspensions of platelet rich plasma (PRP) and resuspended platelets (RSP) by sampling and simultaneous assay on a superfusion cascade (rabbit coeliac artery, rat stomach fundus strip) and on human platelet aggregation. Incubation of prostacyclin in saline led to rapid loss of bioactivity (t1/2 3.2 min); its stability was prolonged in platelet poor plasma (t1/2 25.1 min). However, in PRP and RSP a more spasmogenic product was generated transiently. 6-Keto-PGE1, was 3.0 and 2.5 times more potent on the two bioassay tissues, respectively, but approximately 3 times less so as inhibitor of platelet aggregation. 6-Keto-PGE1 is not extensively metabolised in the isolated perfused rat lung (20.4 or 4.2%, depending on protocol), compared with PGE1 (84.3 or 78.5%), and is a much poorer substrate for the principal prostaglandin metabolising enzyme, prostaglandin 15-hydroxydehydrogenase. These data show that 6-keto-PGE1 is a biologically active but pulmonary-resistant product of prostacyclin metabolism but does not resolve the claim that it might have physiological relevance.

Thromboxane B 2 uptake and metabolism in isolated perfused lung identification and comparison with prostaglandin F 2α

Thromboxane B 2 was metabolised in isolated perfused guinea-pig lungs to a product identified by negative ion chemical ionisation mass spectrometry as 13,14-dihydro-15-ketothromboxane B 2. Conversion was measured by radio TLC and was greater in guinea-pig than rat lungs (29.1 vs. 13.8% at 10 ng/ml), but similar in lungs from normal and sensitized guinea-pigs. Thromboxane B 2 metabolism was less than that of prostaglandin F 2α but, like it, was prevented at 5°C and reduced by cycloheximide pretreatment. Tissue to medium ratio in perfused guinea-pig lungs was 3.4 for thromboxane B 2, but 0.2 for inulin (showing that thromboxane B 2 is accumulated within the lung) and was altered after experimental manipulations. Neither lung slices, crude homogenates, cytosolic and microsomal fractions nor purified prostaglandin 15-hydroxydehydrogenase metabolised thromboxane B 2 in vitro, although prostaglandin F 2α was extensively inactivated. Quantitative partition coefficient and albumin-binding data confirm that thromboxane B 2 lacks prominent lipophilicity, implying that cellular uptake in lung must be carrier-mediated. We conclude that thromboxane B 2 is a substrate for pulmonary degradation which may form a route for the biological inactivation of thromboxane A 2. Its resistance to prostaglandin 15-hydroxydehydrogenase as conventionally tested remains paradoxical and is discussed.

The influence of prostaglandins on sperm motility

Prostaglandin E 2 and F 2α were measured in ejaculates from 10 fertile and 55 infertile men. Prostaglandin F 2α was negatively correlated with motility (r=0.77; p<0.01) in normal men. In patients with disturbed fertility, prostaglandin F 2α was always higher than in the controls, while prostaglandin E 2 was elevated only in patients with persisting varicocele and in those with very low sperm counts and severely impaired motility. There was neither de novo synthesis of prostaglandins in spermatozoa nor were binding sites for prostaglandin E 2 and F 2α detectable. Inactivation of seminal prostaglandins by incubation with prostaglandin 15-hydroxydehydrogenase resulted in a dramatic fall in motility. The results suggest that prostaglandin F 2α act on motility, but the action is not mediated by receptors.

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.

Sulphasalazine analogue Ph CH 44A: Powerful and selective inhibitor of prostaglandin breakdown in vitro and in vivo

Sulphasalazine analogue Ph CH 44A (homosulphasalazine) is a potent inhibitor of prostaglandin inactivation in cell-free 100 000 g supernatants, producing 68.7±6.0% inhibition at 2 μM (7 organs from 2 species) and ID 50 values of 1.6 μM and 5.0 μM in human placenta and rat colon respectively. In the latter organs it was 63 and 20 times more potent than the established prostaglandin 15-hydroxydehydrogenase inhibitor sulphasalazine. Homosulphasalazine is an even weaker inhibitor of prostaglandin synthesis than sulphasalazine , with approximately half the potency on a sheep seminal vesicle preparation. It enhanced prostaglandin synthesis in a 14 000 g supernatant from rabbit kidney medulla. In isolated perfused rat lung homosulphasalazine at 50 μM inhibited prostaglandin F 2α metabolism by 57.9±5.9%. Intravenous infusion of 3.3 μg/kg/min homosulphasalazine in the anaesthetised rat inhibited pulmonary inactivation of intravenous prostaglandin E 1 by 33.3% but did not affect the vasodepressor responses to the prostaglandin when administered intra-arterially.

Sulphasalazine is a potent inhibitor of prostaglandin 15-hydroxydehydrogenase: possible basis for therapeutic action in ulcerative colitis.

Sulphasalazine is a potent and selective inhibitor in vitro of prostaglandin 15-hydroxydehydrogenase in rabbit colon (ID50 = 50 micrometer) and in several other organs of different species, but does not inhibit prostaglandin delta-13 reductase or microsomal prostaglandin synthesis from arachidonic acid. It is suggested that this action may underly the therapeutic usefulness of sulphasalazine in ulcerative colitis for the prevention of relapse.