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Biomedical subjects

F F Sun

Publications and source records attributed to F F Sun.

At least 55 records · Page 3Linked to original sources
PubMed1985

15-Hydroxyeicosatetraenoic acid is a potent inflammatory mediator and agonist of canine tracheal mucus secretion.

It was shown that 15-hydroxyeicosatetraenoic acid (15-HETE) but not 15-H(P)ETE or 5-HETE is a potent agonist for secretion of glycoprotein-containing mucus from the in vivo canine trachea. Given by aerosol into the lungs or by intra-arterial injection into the trachea, 15 HETE also caused the chemotaxis of inflammatory cells into the lumen of the airways. Accompanying this inflammatory cell infiltrate was an increase (183%, p less than 0.05) of expiration of fluid in the partially saturated air coming from the lung. The levels of 15-HETE extracted from tracheal mucus correlated well with hillocks and weight of secreted mucus found in the mucus after hypoxia or after arachidonic acid loading. Indomethacin and atropine blocked the mucus secretagogue effect of 15-HETE in the trachea. Indomethacin and U-52, 412 (a 15-lipoxygenase inhibitor) pretreatment abolished a portion of the 15-HETE-induced enhancement of mucus weight and 15-HETE level in the secretion.

Aerosols↗
PubMed1984

Metabolism of arachidonic acid by human neutrophils. Characterization of the enzymatic reactions that lead to the synthesis of leukotriene B4.

Human neutrophils stimulated with calcium ionophore A23187 synthesized 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene B4. Time-course studies showed that the concentrations of both products reached a maximum after 2 min after which the products were rapidly removed. In longer incubations, 5-HETE was esterified into membrane lipids, and leukotriene B4 was converted to 20- hydroxyleukotriene B4 and/or 20- carboxyleukotriene B4. The reaction is apparently self-limiting. After the maximum was reached, addition of fresh ionophore, Ca2+ or oxygen had little effect. Fresh arachidonic acid increases the yields of 5-HETE and delta 6-trans-leukotriene B4 but not additional leukotriene B4. Only the addition of fresh neutrophils gave additional leukotriene B4. This finding suggests that leukotriene B4 synthesis is limited by both substrate availability and enzyme inhibition by hydroperoxide intermediate. Exogenous arachidonic acid added with ionophore had different effects on the syntheses of leukotriene B4, delta 6-trans-leukotriene B4, and 5-HETE. As the arachidonic acid concentration increases, product formation increases in the following order: 5-HETE greater than delta 6-trans-leukotriene B4 greater than leukotriene B4. At a high concentration (more than 10 microM) of arachidonic acid, the synthesis of delta 6-trans-leukotriene B4 was greater than leukotriene B4 itself. Since delta 6-trans-leukotriene B4 represents the nonenzymatic decomposition of leukotriene A4, we suggest that one of the rate-limiting steps in the synthesis of leukotriene B4 is the leukotriene A4 hydrolase. Our data suggest the synthesis of leukotriene B4 is under the control of three factors: (1) substrate availability; (2) limited capacity of the leukotriene A4 hydrolase, and (3) enzyme inactivators generated during the reaction, such as hydroperoxide intermediate. The tightly controlled system assures only a finite amount of this powerful bioactive substance will be produced under most conditions.

Arachidonic Acid↗
PubMed1984

Oxidation of prostacyclin and its analogs by three 15-hydroxyprostaglandin dehydrogenases.

A study of the oxidation of prostacyclin and some of its analogs by three 15-hydroxyprostaglandin dehydrogenases was undertaken to determine the structural features of these compounds which might influence their rate of enzymatic inactivation. The effect of some structural changes seemed to be determined by the substrate specificity of individual enzymes. Other changes influenced the rate of oxidation by all three enzymes similarily. Among this latter group it was noted that a 15S hydroxyl group is necessary for oxidation to occur and that steric changes in the carboxy side chain and structural changes in the epoxy ring have a greater effect on the affinity of the substrate for the enzyme than on its maximum rate of oxidation. Certain analogs of prostacyclin are not substrates for one or more of the enzymes tested. Of these, (5S)-9-deoxy-5,9 alpha-epoxy-PGF1 and its methyl ester are potent inhibitors of only the placental enzyme---an interesting case of apparent selective metabolic regulation.

Animals↗
PubMed1983

Inhibition of human neutrophil arachidonate 5-lipoxygenase by 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1 (U-60257).

6,9-Deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1 (U-60257) and its methyl ester (U-56467) are selective inhibitors of leukotriene C and D biosynthesis both in vitro and in vivo. In this study, we demonstrated that the principal site of inhibition may be arachidonate 5-lipoxygenase, the initial enzyme of leukotriene biosynthesis. U-60257 and its methyl ester block LTB4 synthesis in human peripheral neutrophils with an ID50 of 1.8 and 0.42 microM respectively. This inhibitory action of U-60257 on neutrophil 5-lipoxygenase can be reduced or reversed by a high concentration of exogenous arachidonic acid. U-60257 at 100 microM has no apparent effect on the following enzymes. 1) cyclooxygenase of sheep vesicular gland or human platelets; 2) 12-lipoxygenase of human platelets and 3) soybean 15-lipoxygenase. Thus, we conclude that U-60257 and its methyl ester are potent and selective inhibitors of arachidonate 5-lipoxygenase.

Arachidonate Lipoxygenases↗
PubMed1983

Circulating prostacyclin metabolites in the dog.

The present study was designed to determine the concentration of prostacyclin (PGI2) metabolites in the blood of the dog. After a bolus i.v. dose of [11 beta-3H]PGI2 (5 micrograms/kg) into each of five dogs, blood samples were withdrawn at 0.33, 0.67, 1, 3, 5, 20, 30, 60 and 120 min postdrug administration. Plasma samples were extracted and the radioactive components were analyzed by two-dimensional thin-layer chromatography with autoradiofluorography and radio-high-performance liquid chromatography. The compounds were identified by comparing their mobility with synthetic standards; only parallel responses observed in both tests constituted positive identification. Seven metabolites were identified by these two techniques: 6-keto-prostaglandin (PG)F1 alpha; 6-keto-PGE1; 2,3-dinor-6-keto-PGF 1 alpha; 2,3-dinor-13,14-dihydro-6,15-diketo-20-carboxyl PGF 1 alpha; and 2,3,18,19-tetranor-13,14-dihydro-6,15-diketo-20-carboxyl PGF 1 alpha. Several additional compounds, both polar and nonpolar in nature, which did not co-chromatograph with any of our standards were also detected. Early samples consisted predominantly of 6-keto-PGF 1 alpha and other 20-carbon metabolites. By 30 min, the predominant metabolites were the 16- and 18-carbon dicarboxylic acids. By 60 min, 85% of the radioactivity was associated with two unidentified polar compounds. The evidence suggests that 6-keto-PGF 1 alpha probably reflects only the transient levels of freshly entering PGI2 in the circulation, whereas levels of the most polar metabolites (e.g., dihydro-diketo-carboxyl tetranor-PGF 2 alpha) may be a better measure of the overall PGI2 presence due to its longer half-life in circulation.

Animals↗
PubMed1982

6,9-deepoxy-6,9,-(phenylimino)-delta 6,8-prostaglandin I1, (U-60,257), a new inhibitor of leukotriene C and D synthesis: in vitro studies.

Addition of the calcium inophore, A 23187, and cysteine to isolated mononuclear cells from rat peritoneal washings causes a marked increase in the formation of thromboxane B2 (TxB2) along with the formation of leukotrienes C and D (LT's). The formation of LT's in this system was inhibited by 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1, U-60,257, or its methyl ester, U-56,467, (ID50 4.6 and 0.31 microM, respectively). There was no inhibition of TxB2 formation. By contrast, two structurally-related compounds, PGI2 and its stable analog, 6-beta-PGI1, did not affect the formation of either LT's or TxB2. The inhibition of LT formation by U-60,257 was rapidly reversed after removal of this compound from the cells. U-60,257 did not inhibit the cyclooxygenase of human polymorphonuclear leukocytes. Nor did it inhibit formation of 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) in human platelets. On the other hand, U-60,257 inhibited glutathione S-transferase activity of rat basophil leukemia cells (ID50, 37 microM), suggesting that this compound may inhibit the last step in LTC biosynthesis. In addition to inhibiting LT synthesis, U-60,257 also appears to be a competitive inhibitor of the action of LT on the guinea pig ileum, although this inhibition requires a higher drug concentration than those ordinarily encountered during assay for LT's in U-60,257-treated incubations.

Animals↗
PubMed1981

Metabolism of (5E)-6a-carbaprostaglandin I2 by rhesus monkey lung 15-OH prostaglandin dehydrogenase.

(5E)-6a-Carbaprostaglandin I2 (carbacyclin) was oxidized to (5E)-15-dehydro-6a-carbaprostaglandin I2 (15-dehydrocarbacyclin) by partially purified rhesus monkey lung prostaglandin dehydrogenase (PGDH). The (5E-15-dehydro-6a-carbaprostaglandin I2 was isolated by preparative thin-layer chromatography and identified by gas chromatography-mass spectrometry. A Lineweaver-Burke plot gave an apparent Km value of 2.9 microM and a Vmax of 35.7 nmoles carbacyclin oxidized/mg protein/min. These values are similar to previously reported Km and Vmax values for PGI2 and PGE1.

Animals↗
PubMed1981

Arachidonate metabolism in the mouse thyroid implication of the lipoxygenase pathway in thyrotropin action.

The present study of compares the effects of various inhibitors of arachidonate metabolism on mouse thyroid cyclo-oxygenase and lipoxygenase activities and thyrotropin-augmented cyclic-AMP accumulation. Mouse thyroid homogenate converts [1-14C]- arachidonate to several products of the cyclo-oxygenase pathway as well as one major product of the lipoxygenase pathway, 12-L-hydroxyeicosatetraenoic acid (12-Hete). Prostaglandin (PG) formation in thyroid homogenates is inhibited by 1-10 microM indomethacin and etya. 12-HETE accumulation is reduced by 91%, 83% and 20% by 5 microM ETYA, 15-HETE, and indomethacin, respectively. Thyrotropin-stimulated cyclic-AMP accumulation, measured in whole thyroid lobes by radioimmunoassay, is reduced by 45% and 73% by 50 microM and 100 microM ETYA, respectively; indomethacin is without effect at these concentrations. 15-HETE reduces thyrotropin-augmented cyclic-AMP accumulation by 57% and 100 microM. In product inhibition studies, 10 microM 12-HETE reduced the formation of radiolabeled 12-HETE by 20%. 10 microM PGE2, PGF2 alpha or PGD2 had no effect on [1-14C]-PG formation. 12-HETE, however, reduced PG synthesis by 76% at 10 microM. This is the first report implicating the arachidonate lipoxygenase pathway in thyrotropin action at the level of cyclic-AMP regulation. Additionally, our finding that 12-HETE inhibits prostaglandin synthesis suggests that the cyclo-oxygenase and lipoxygenase pathways in the mouse thyroid may be highly integrated.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1981

Metabolism of prostacyclin in Cynomolgus monkey.

The metabolism of prostacyclin (PGI2) in vivo was investigated in Cynomolgus monkey. Following intravenous infusion of 11-[3H]-PGI2 for three days, pooled urine was extracted with Amberlite XAD-2, then chromatographed and purified by Sephadex LH-20, and reverse phase column chromatography. Radioactive fractions were converted to appropriate derivatives for identification by gas chromatography mass spectrometry. Twelve metabolites were characterized, the major of which was 6-keto-PGF1 alpha, accounting for 13% of the urinary radioactivity. The metabolic pathways are similar to those observed earlier in the rat. The excretion of substantial amounts of unchanged 6-keto-PGF1 alpha indicated that the monkey was not able to metabolize PGI2 as avidly as the rat.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Inhibition of platelet arachidonic acid 12-lipoxygenase by acetylenic acid compounds.

Eighteen acetylenic fatty acids were tested as inhibitors of human platelet arachidonic acid 12-lipoxygenase. 4,7,10,13-Eicosatetraynoic (4,7,10,13-ETYA) acid emerged as the most potent compound. Additional experiments have shown that 4,7,10,13-ETYA selectively blocked the 12-lipoxygenase in washed human platelets with lesser activity against the cyclooxygenase. The ID50 value for lipoxygenase was 7.8 microM in comparison with an ID50 of 100 microM for the cyclooxygenase. The commonly used inhibitor 5,8,11,14-eicosatetraynoic acid inhibited both enzymes with equal potency. It appears that 4,7,10,13-ETYA may be a valuable lead for selective modulation of the 12-lipoxygenase pathway in platelet or other target tissues.

5,8,11,14-Eicosatetraynoic Acid↗