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Effect of Salicylates on Histamine and L-Histidine Metabolism. Inhibition of Imidazoleacetate Phosphoribosyl Transferase

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Effect of Salicylates on Histamine and L-Histidine Metabolism. Inhibition of Imidazoleacetate Phosphoribosyl Transferase Effect of salicylates on histamine and L-histidine metabolism. Inhibition of imidazoleacetate phosphoribosyl transferase. J Moss, … , M Vaughan, M A Beaven J Clin Invest. 1976;58(1):137-141. https://doi.org/10.1172/JCI108442. Research Article In man and other animals, urinary excretion of the histidine and histamine metabolite, imidazoleacetate, is increased and that of its conjugated metabolite, ribosylimidazoleacetate, decreased by salicylates. Imidazoleacetate has been reported to produce analgesia and narcosis. Its accumulation as a result of transferase inhibition could play a part in the therapeutic effects of salicylates. To determine the locus of salicylate action, we have investigated the effect of anti- inflammatory drugs on imidazoleacetate phosphoribosyl transferase, the enzyme that catalyzes the ATP-dependent conjugation of imidazoleacetate with phosphoribosylpyrophosphate. As little as 0.2 mM aspirin produced 50% inhibition of the rat liver transferase. In vivo, a 30% decrease in the urinary excretion of ribosylimidazoleacetate has been observed with plasma salicylate concentrations of 0.4 mM. The enzyme was also inhibited by sodium salicylate but not by salicylamide, sodium gentisate, aminopyrine, phenacetin, phenylbutazone, or indomethacin. The last four drugs have been shown previously not to alter the excretion of ribosylimidazoleacetate when administered in vivo. Since both the drug specificity and inhibitory concentrations are similar in vivo and in vitro, it seems probable that the effect of salicylates on imidazoleacetate conjugation results from inhibition of imidazoleacetate phosphoribosyl transferase. Find the latest version: https://jci.me/108442/pdf Effect of Salicylates on Histamine and L-Histidine Metabolism INHIBITION OF IMIDAZOLEACETATE PHOSPHORIBOSYL TRANSFERASE JOEL MOSS, MARIA C. DE MELLO, MARTHA VAUGHAN, and MICHAEL A. BEAVEN From the Laboratory of Cellular Metabolism and the Pulmonary Branch, National Heart and Lung Institute, Bethesda, Maryland 20014 A B ST R A CT In man and other animals, urinary ex- phosphate in an ATP-dependent reaction (7, 8). In our cretion of the histidine and histamine metabolite, imi- previous studies (9), administration of therapeutic doses dazoleacetate, is increased and that of its conjugated of salicylates in humans resulted in a decrease in the metabolite, ribosylimidazoleacetate, decreased by salicyl- urinary excretion of ribosylimidazoleacetate with a con- ates. Imidazoleacetate has been reported to produce comitant increase in the excretion of free imidazoleace- analgesia and narcosis. Its accumulation as a result of tate. Because of the reported analgesic and narcotic transferase inhibition could play a part in the therapeutic action of imidazoleacetate (10, 11) and the possibility effects of salicylates. To determine the locus of salicylate that salicylates may exert their analgesic effects through action, we have investigated the effect of anti-inflamma- alteration in the metabolism of imidazoleacetate, we have tory drugs on imidazoleacetate phosphoribosyl transfer- investigated further the locus of salicylate action. The ase, the enzyme that catalyzes the ATP-dependent conju- work described in this report will show that aspirin, but gation of imidazoleacetate with phosphoribosylpyrophos- not the nonsalicylate anti-inflammatory drugs, inhibits phate. As little as 0.2 mM aspirin produced 50% inhibi- the partially purified imidazoleacetate phosphoribosyl tion of the rat liver transferase. In vivo, a 30% decrease transferase, the enzyme that catalyzes the formation of in the urinary excretion of ribosylimidazoleacetate has phosphoribosylimidazoleacetate from imidazoleacetate.1 It been observed with plasma salicylate concentrations of 0.4 appears that salicylates block the metabolism of imi- mM. The enzyme was also inhibited by sodium salicylate dazoleacetate in vivo by inhibiting imidazoleacetate but not by salicylamide, sodium gentisate, aminopyrine, phosphoribosyl transferase. phenacetin, phenylbutazone, or indomethacin. The last 1 The mechanism of conjugation in vivo has not been four drugs have been shown previously not to alter the defined. Crowley (7) has demonstrated that, in the presence excretion of ribosylimidazoleacetate when administered of ATP and phosphoribosylpyrophosphate (PRPP), soluble in vivo. Since both the drug specificity and inhibitory fractions from extraots of rat liver catalyze the formation of concentrations are similar in vivo and in vitro, it seems phosphoribosylimidazoleacetate (ImARP) from imidazole- probable that the effect of salicylates on imidazoleacetate acetate (ImA) according to the following reaction. conjugation results from inhibition of imidazoleacetate imidazoleacetate phosphoribosyl transferase. ImA + ATP + PRPP phosphoribosyl transferase INTRODUCTION ImARP + ADP + Pi + PPi. A principal urinary metabolite of L-histidine (1) and The phosphoribosylimidazoleacetate is thought to be con- histamine (2-6) in humans and other species is 1- verted to the urinary excretion product, ribosylimidazole- ribosylimidazole-4-acetate, which is formed by conjuga- acetate, by the action of phosphatase(s). The present finding tion of imidazole-4 (5)-acetate with phosphoribosylpyro- that salicylates inhibit the conjugation of imidazoleacetate in vivo as well as the above reaction.in vitro strongly suggests Received for publication 21 November 1975 and in rezised that the enzyme system described by Crowley is involved in form 2 February 1976. the conjugation in vivo. The Journal of Clinical Investigation Volume 58 July 1976 -137-141 137 A B C was purchased from Amersham/Searle Corp., Arlington 10,750 cpm Heights, Ill. Unlabeled histamine metabolites were obtained from sources described earlier (9). Acid phosphatase (po- 9,700 cpm tato, grade B) was obtained from Calbiochem, San Diego, Calif. and pyruvate kinase from Sigma Corporation, San Diego, Calif. Purification of imidazoleacetate phosphoribosyl transferase. Male Osborne Mendel rats were anesthetized with ether. A midline abdominal incision was made, the portal vein catheterized, and the inferior vena cava severed. The portal E vein was flushed with 0.25 M sucrose containing 50 mM 01,000- Tris (Cl-), pH 7.5. After decapitation of the rat, the liver was excised, minced finely with a razor blade, and homoge- nized (10 strokes) with a tight-fitting ground-glass homoge- nizer in 5 volumes of 20 mM potassium phosphate, 5 mM 6.3% MgClI, 1 mM EDTA, pH 7.5, at 0-4'C. The homogenate 500 was filtered through two layers of cheesecloth and centri- 4.5% fuged at 100,000 g for 40 min. The supernatant fraction was stirred with an equal volume of DEAE-cellulose which had been previously equilibrated with 5 mM potassium phos- phate, 1 mM EDTA, pH 7.0. After centrifugation at 5,000 g 0.8 for 30 min, the supernatant fraction was discarded. The DEAE-cellulose was then washed three times by stirring with 5 volumes of the same buffer for 30 min. The washed FIGURE 1 Thin layer chromatography of labeled substrate DEAE-cellulose was extracted with 5 volumes of 1 mM and reaction products in incubations of DEAE-cellulose EDTA in 0.5 mM potassium phosphate buffer, pH 7.0, for purified rat liver imidazoleacetate phosphoribosyl transfer- 30 min and the extract centrifuged at 5,000 rpm for 10 min ase. Chromatograms (Solvent A) of: (A) reaction mix to remove cellulose fibers. The enzyme was prepared on without enzyme; (B) reaction mix with enzyme; and (C) the day of the experiment. reaction mix with enzyme after further incubation with Assay of imidazoleacetate phosphoribosyl transferase. acid phosphatase. Radioactivity was determined in 2.5-mm The standard assay mixture contained 0.4 mM imidazoleace- segments of the chromatogram. 4.0 0 METHODS Materials. Drugs were obtained from the following sup- pliers: Acetylsalicylic acid powder USP, Mallinckrodt Inc.. St. Louis, Mo.; sodium salicylate, USP, Aldrich Chemical Co., Inc., Milwaukee, Wisc.; phenylbutazone, Geigy Phar- 3.0 maceuticals, Ardsley, N. Y.; phenacetin, Eastman Kodak Co., Rochester, N. Y.; indomethacin, Merck Sharp & Dohme, Rahway, N. J.; salicylamide and aminopyrine, Gil- z man Inc., Washington, D. C.; and sodium gentisate (2,5- 0 dihydroxybenzoic acid, sodium salt), Nutritional Biochemi- En cals Corp., Cleveland, Ohio. Solutions of the drugs were 2.0 adjusted to pH 7.4 before use. Reagents were obtained from z the following sources: 5-phosphorylribose-1-pyrophosphate 0 dimagnesium dihydrate, Boehringer Mannheim Corp., Bio- 0- chemical Div., New York; ATP, phosphoenol pyruvate, Trizma base, and ribose-5-phosphate, Sigma Chemical Co., St. Louis, Mo.; EDTA and potassium phosphate from 1.0 Fisher Scientific Co., Pittsburgh, Pa.; sodium dodecyl sul- fate from Schwarz/Mann Div., Becton, Dickinson & Co., Orangeburg, N. Y.; and DE 23 (DEAE-cellulose from Whatman Chemicals, Div. W & R Balston, Maidstone, Kent, England). The DEAE was equilibrated by washing 250 g with 0.5 M NaOH, water (until neutral); 0.5 M HCI, water (until neutral); 0.5 M potassium phosphate, pH 0 10 20 40 60 7.0; and 5 mM potassium phosphate, 1 mM EDTA, pH TIME (min) 7.0 (final volume 2 liters). Polygram Cel, thin layer cellu- lose-coated (0.1-mm) plastic sheets (5 x 20 cm) were pur- FIGuRE 2 Time course of conversion of [8H]imidazoleace- chased from Macherey-Nagel and Co., Duren, W. Germany. tate to [3H]phosphoribosylimidazoleacetate by the rat liver [3H]Imidazoleacetic acid, 1.3 Ci/mmol, prepared from un- imidazoleacetate phosphoribosyl transferase and the effect of labeled imidazoleacetic
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