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9-Deoxy-A9,A12-13,14 Proc. Natl. Acad. Sci. USA Vol. 81, pp. 1317-1321, March 1984 Biochemistry 9-Deoxy-A9,A12-13,14-dihydroprostaglandin D2, a metabolite of prostaglandin D2 formed in human plasma (dehydration product of prostaglandin D2/serum albumin/cell growth inhibition) YOSHIHARU KIKAWA*, SHUH NARUMIYA*, MASANORI FUKUSHIMAt, HIROHISA WAKATSUKAt, AND OSAMU HAYAISHI§ *Department of Medical Chemistry, Kyoto University Faculty of Medicine, Sakyo-ku, Kyoto 606, Japan; tDepartment of Internal Medicine and Laboratory of Chemotherapy, Aichi Cancer Center, Chikusa-ku, Nagoya 464, Japan; tResearch Institute, Ono Pharmaceutical Co., Shimamoto, Mishima, Osaka 618, Japan; and §Osaka Medical College, Daigaku-cho, Takatsuki, Osaka 569, Japan Contributed by Osamu Hayaishi, November 8, 1983 ABSTRACT Incubation of prostaglandin D2 (PGD2) with from Sigma. Dimethylisopropylsilyl (Me2iPrSi) imidazole human plasma yielded a product that has been identified as 9- and methoxyamine hydrochloride were from Tokyo Kasei deoxy-9,10-didehydro-12,13-cdidehydro-13,14-dihydro-PGD2 (Tokyo). Sep-pak silica and Sep-pak C18 cartridges were (9-deoxy-_9,9'2-13,14-dihydro-PGD2). The identification was from Waters Associates. Precoated silica gel plates [G60- based on mass spectrometry, UV spectrometry, mobilities and (F254)] with concentration zones and silica gel 60 for column retention time on TLC and HPLC, and NMR. The conversion chromatography were from Merck. Sephadex LH-20 was a of PGD2 to this product was dependent on the incubation time product of Pharmacia. Solvents used in the extraction of and the amount of plasma added to a reaction mixture and was PGD2 metabolites for identification were distilled before use. abolished by prior boiling. The conversion rate ofPGD2 to this All other chemicals were of reagent grade. metabolite was 0.03 nmol/min per mg of protein of whole plas- Pregaration of 9-Deoxy-A9,Al2-13,14-dihydro-PGD2. 9-De- ma at pH 8.0 at 37°C. Similar conversion was also found by oxy-A -GD2 was synthesized as described (12), and conver- incubating PGD2 with human serum albumin added at the sion of 9-deoxy-A9-PGD2 to 9-deoxy-A9,A&12-13,14-dihydro- concentration found in plasma. These results suggest that the PGD2 was carried out as described by Bundy et al. (13) for conversion of PGD2 to this product is catalyzed by the enzy- the conversion of PGD2 to A12-13,14-dihydro-PGD2. 9- matic action of a plasma protein, probably serum albumin. Deoxy-A9-PGD2 (48 mg) was dissolved in 3 ml of tetrahydro- The biological activities of this compound were examined in furan and the solution was stirred at 4°C. 1,5-Diazabicy- several systems. It showed negligible activity in inhibition of clo(4.3.0)non-5-ene (17.8 mg) in 0.18 ml of tetrahydrofuran human platelet aggregation and relaxation of rabbit stomach was added to the solution and the mixture was stirred at strip. On the other hand, it exhibited a three times stronger room temperature overnight. The mixture was diluted with inhibitory activity (IC50, 1.8 ,M) than PGD2 (IC50, 5 ,uM) on 30 ml of water, and the product was separated out by extrac- the growth of L-1210 cultured cells. tion with 50 ml of ethyl acetate. The ethyl acetate extract was washed successively with 1.2 M hydrochloric acid, Prostaglandin (PG) D2 is formed in a variety of tissues and three times with excess water, and finally with a saturated cells and modulates their functions under various physiologi- NaCl solution. After being dried over anhydrous MgSO4 and cal and pathological conditions. For example, it is produced concentrated in vacuo, the crude product was purified in sili- during platelet aggregation and works as a negative feedback ca gel column chromatography (30 g of silica gel 60) with a modulator of the aggregation process (1-3). It is produced by solvent of ethyl acetate/n-hexane/methyl alcohol (50:50:2) and modifies the anaphy- to afford 9 mg of 9-deoxy-A9,Al2-13,14-dihydro-PGD2 as a mast cells during IgE stimulation colorless oil; Rf, 0.36 (silica gel TLC with ethyl acetate/ben- laxis process (4, 5). It is also produced in the central nervous zene/acetic acid, 50:50:2); IR, 2930, 1700, 1640, 1580, 1232, system of mammals and is involved in brain functions such dd 6.56 as hypothermia, sleep, and luteinizing hormone secretion (6- and 1028 cm-1; NMR (C2HCl3), 6 7.5 (1H, C9 H), 10). A potential antineoplastic effect of PGD2 has been re- (1H, t, C13 H), 6.35 (1H, dd, C10 H), 5.48 (2H, m, C5,C6 H), ported (11) and it has been found that 9-deoxy-A9-PGD2, a 3.88 (1H, m, C15 H), and 3.44 (1H, m, C8 H); mass spectrum dehydration product ofPGD2, has about three times stronger (direct inlet), ions at m/z 334 (M), 316, 245, and 236; UV L-1210 leukemia cul- (EtOH) Xmax 244 nm (e 6100). growth inhibitory effect than PGD2 on Preparation of Human Plasma. Blood, 50 ml, was obtained tured cells (12). The present study was undertaken to ex- ml plore the possible formation of this PGD2 dehydration prod- from a healthy volunteer into a plastic tube containing 5 here the conversion in human of 3.8% sodium citrate, and the mixture was centrifuged at uct in mammals. We report 1000 x g for 15 min. Plasma was then dialyzed against two plasma of PGD2 to a compound that has been identified as 9- at 7.4 and describe some prop- changes of 2 liters each of 50 mM Tris HCl buffer pH deoxy-A9,A12-13,14-dihydro-PGD2 or pH 8.0. erties of this metabolite.$ Enzyme Assay. Enzymatic activity was assayed as follows. MATERIALS AND METHODS The standard mixture contained 150 uM [3H]PGD2 (4000 cpm/nmol), dialyzed plasma, and 50 mM Tris HCl buffer Materials. [5,6,8,9,12,14,15-3H]PGD2 (100 Ci/mmol; 1 Ci (pH 7.4 or pH 8.0) in a final reaction volume of 0.4 ml. Reac- = 37 GBq) was purchased from New England Nuclear. tions were carried out by incubating the mixture at 37°C with PGB2, PGD2, and 9-deoxy-A9-PGD2 were synthetic products constant shaking and terminated by acidification with 1 M from Ono Pharmaceutical (Osaka, Japan). Human serum albumin (fatty acid free) was from Miles. ADP was obtained Abbreviations: PG, prostaglandin; Me2iPrSi, dimethylisopropyl- silyl; GC/MS, gas chromatography/mass spectrometry. The publication costs of this article were defrayed in part by page charge part of this work was presented at the Fifty-Sixth Annual Meeting payment. This article must therefore be hereby marked "advertisement" of the Japanese Biochemical Society, Sept. 29-Oct. 2, 1983, Fuku- in accordance with 18 U.S.C. §1734 solely to indicate this fact. oka, Japan. 1317 Downloaded by guest on October 4, 2021 1318 Biochemistry: Kikawa et at Proc. NatL Acad Sci. USA 81 (1984) HCl to pH 3.0. The acidified mixture was directly applied on Tokyo). Compounds were dissolved in ethanol at a concen- a Sep-pak C18 cartridge, and products were eluted with 10 ml tration of 1 mg/ml and diluted with 50 mM TrisHCl (pH 8.0) of ethyl acetate as described (14). After evaporation in vac- before application. Platelet aggregometry was carried out us- uo, the residues were dissolved in 50 1.d of ethyl ether and ing an aggregometer Hematracer 1 model PAT 2M (Niko applied 2 cm wide on a silica gel thin layer. Authentic PGB2, Bioscience, Tokyo) as described (17). Inhibition of L-1210 PGD2, 9-deoxy-A9-PGD2, and 9-deoxy-A9,A'2-13,14-dihy- cell growth was examined as described (11). dro-PGD2 were applied as markers at least 2 cm away from Miscellaneous. UV absorption spectra were recorded on a the samples. TLC was carried out with a solvent of ben- Shimadzu UV300 spectrophotometer. NMR was recorded in zene/ethyl acetate/acetic acid (50:50:2). After development, C2HCl3 with a Varian NMR spectrometer XL-200. Protein radioactive zones on the TLC plates were located by a ra- concentration was determined according to the method of diochromatogram scanner Packard model 7201, and markers Lowry et al. (18) with bovine serum albumin as standard. were visualized by exposure to iodine vapor. Silica gel zones corresponding to PGD2, 9-deoxy-A9,A12-13,14-dihydro- RESULTS PGD2, and 9-deoxy-A9-PGD2 were scraped, respectively, Formation and Identification of 9-Deoxy-&9,A1213914dihy- and the rest of the silica gel was scraped altogether. Radioac- dro-PGD2. When PGD2 was incubated with dialyzed human tivity in the silica gel was measured with a Packard liquid plasma, it was converted to two products (Fig. 1). The major scintillation spectrometer (model 460C) in a toluene scintilla- product (compound 2) accounted for more than 80% of the tor. Since 3H at position 12 was lost during conversion of total amount of products, while the minor product (com- PGD2 to 9-deoxy-A9,A12-13,14-dihydro-PGD2, quantification pound 1) accounted for only 10%. Boiling of plasma marked- of the latter compound was carried out on the basis of the ly decreased the formation of compound 2 but did not affect specific activity corrected for the loss of this tritium. the formation of compound 1 significantly. These results Isolation of 9-Deoxy-A,9 A2-13,14-dihydro-PGD2. The reac- suggest that compound 2 is formed by the enzymatic action tion product, 9-deoxy-A ,A 2-13,14-dihydro-PGD2, was iso- of human plasma while compound 1 is a nonenzymatically lated on a large scale.
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