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1.
The effects of imidazole, 1-methyl-imidazole and benzimidazole on bone metabolism were investigated. The relative potencies of these compounds with respect to the inhibition of bone resorption was found to be comparable to their relative effectiveness as inhibitors of platelet microsome thromboxane synthetase activity. Since studies by others have shown that thromboxanes are produced by resorbing bone , these results suggest that the inhibition of bone resorption by imidazole is related to the inhibition of thromboxane A2 formation. This could imply that thromboxane A2 is an additional arachidonic acid oxidation product that is of importance in the regulation of bone metabolism. 相似文献
2.
R.A. Waterman 《Prostaglandins & other lipid mediators》1980,20(1):73-85
The effects of Cloprostenol administration on porcine luteal lipid and arachidonic acid accumulation were examined in relation to luteal progesterone and prostaglandin F synthesis in 18 mature gilts at day 12 of the estrous cycle. Basal and net release of progesterone from luteal tissue was depressed at 8 hr after treatment whereas net release of prostaglandin F was elevated at 8 hr. Inclusion of copper dithiothreitol or reduced glutathione in the incubation media resulted in minor alterations of release of progesterone and prostaglandin F and no changes in composition of luteal lipids or fatty acids. Luteal contents of triglyceride had increased by 8 hr after treatment whereas contents of free and esterified cholesterols had increased by 32 hr after Cloprostenol administration. Luteal contents of phospholipid and free fatty acids were not affected by Cloprostenol administration. At 32 hr after treatment, percentages and content of arachidonic acid had increased in luteal cholesterol esters and triglycerides. Although arachidonic acid percentages increased in luteal free fatty acids and phospholipids, calculated arachidonic acid contents did not change following Cloprostenol administration. Induced luteal regression was associated with decreased progesterone release, increased prostaglandin F release, and accelerated lipid and arachidonic acid accumulation within the corpus luteum. The effects of altered lipid metabolism on release of prostaglandin F could not be defined. However, availability of arachidonic acid did not appear to be rate-limiting in relation to luteal prostaglandin F synthesis. 相似文献
3.
Active tension is produced by the lower esophageal sphincter (LES) of North American opossum by a myogenic mechanism. Strips of LES, but not those from the esophageal body, contracted to prostaglandin (PG)F2α, stable expoxymethano derivatives of PGH2 and to thromboxane B2. Stable endoperoxides were more than 500 times more potent than PGF2α. PGI2 and 6-keto PGF1α were weak relaxants of LES strips. LES strips transformed arachidonic acid into contractile substances. This transformation was prevented by agents which interfere with PG synthesis by inhibiting cyclo-oxygenase [indomethacin (IDM), 5,8,11,14-eicosatetraynoic acid (ETA) or thromboxane synthetase [imidazole]. Tranylcypromine 500 μg/ml also inhibited contractions to arachidonic acid. These agents also reduced muscle tone, so that endogenous PG formation may contribute to active tension in the LES. ETA and IDM increased tone before inhibiting it, and this effect was prevented by prior treatment with ETA or imidazole. There may also be an endogenous PG which inhibits LES tone. The possibility that this may be PGI2 is discussed. 相似文献
4.
The present studies were undertaken to examine the hypothesis that ethanol could effect cellular biosynthesis in the murine mastocytoma cell of prostaglandins and leukotrienes, oxidative metabolites of arachidonic acid, at concentrations that could be encountered as well as during experiments. The effects of ethanol which encompass these concentration ranges (200–1000 mg%) can be summarized as follows: first in the absence of exogenous arachidonic acid, ethanol caused a dose dependent decrease in the production of leukotrienes which was statistically significant at 200 mg%. At 1000 mg%, ethanol caused a 20–50% decrease in leukotrienes and a 21% decrease in the amount of prostaglandins D2 (PGD2) formed in these cells. Secondly, when cells were incubated with exogenous arachidonic acid (14 μg/ml), large increases in both PGD2 and leukotrienes occurred. Under these conditions, ethanol caused a further increase in the amount of leukotrienes and a small increase in the amount of PGD2 formed. This stimulatory effect was specific for ethanol since neither t-butanol nor n-butanol caused the enhanced production of leukotrienes with exogenous arachidonic acid. Thus, these experiments sugsests that ethanol affects metabolsim of arachidonic acid at reasonably low doses (200–400 mg%) of ethanol in a manner dependent on the free arachidonic acid in the tissue. Also, experiments in which ethanol is used as a solvent for arachidonic acid could be greatly affected by high levels of ethanol (500–1000 mg%) which are frequently utilized. 相似文献
5.
Edmond C. Ku Stephen E. McPherson Carol Signor Herbert Chertock William D. Cash 《Biochemical and biophysical research communications》1983,112(3):899-906
CGS 13080 inhibited cell-free thromboxane synthetase with an IC50 of 3 nM. It was at least five orders of magnitude less potent toward other key enzymes involved in arachidonic acid metabolism. Submicromolar concentrations inhibited calcium ionophore-induced formation of thromboxane B2 by intact human platelets with concomitant accumulation of prostaglandin E2. Oral doses lower than 1 mg/kg in rats suppressed the elevations of plasma thromboxane B2 induced by calcium ionophore. This was attended by shunting of endoperoxide substrate to 6-keto-prostaglandin F1α and prostaglandin E2. CGS 13080 is one of the most potent and selective thromboxane synthetase inhibitors yet identified. 相似文献
6.
Relationships between perinatal mortality, disrupted uteroplacental function and prostaglandin metabolism have been studied in Zn-deficient rats. Uterine contractility , placental blood flow , and uterine and placental prostaglandin synthesis from [1?14C] arachidonic acid were investigated at day 22 of pregnancy. High amplitude uterine contractions were almost completely eliminated and utero-placental blood flow was decreased by 85% by Zn deficiency. Synthesis of [1?14C]-prostaglandin E2, F2α and 6-keto-F1α from [1?14C] arachidonic acid decreased significantly in uterine tissue but increased in placentae. These possibly inter-related effects may contribute to the high perinatal mortality observed in Zn deficiency. 相似文献
7.
K Werkmeister F Wieland E Schweizer 《Biochemical and biophysical research communications》1980,96(1):483-490
A mixture of two pantetheine-free mutant fatty acid synthetases was dissociated and recombined to form a hybrid apoenzyme complex. the corresponding -mutants exhibit interallelic complementation when crossed with each other and the enzyme synthesized in the resulting diploid contains pantetheine and exhibits overall fatty acid synthetase activity. Accordingly, the hybrid apoenzyme formed could be activated to holo-fatty acid synthetase when incubated with coenzyme A and a partially purified yeast cell extract. The enzyme coenzyme A: fatty acid synthetase apoenzyme 4′-phosphopantetheine transferase has thus been identified in yeast. Further studies on the mechanism of fatty acid synthetase holoenzyme formation will now be possible. 相似文献
8.
U. Zor B. Strulovici A. Nimrod H.R. Lindner 《Prostaglandins & other lipid mediators》1977,14(5):947-959
Rat Graafian follicles isolated intact responded to 8-Br-cyclic AMP and 8-Br-cyclic GMP with increased prostaglandin E (PGE) production during a 6 h incubation. By contrast, 8-Br-cyclic IMP, 8-Br-5′ AMP and 8-Br-5′ GMP were inactive in this respect. The effect of 8-Br-cyclic AMP and 8-Br-cyclic GMP was noted only after a lag period of about 4 h. Choleragen, LH, and the phosphodiesterase inhibitor (3-isobutyl-1-methyl-xanthine; IBMX) also stimulated PGE production. Actinomycin D and cycloheximide given simultaneously with 8-Br-cyclic AMP or LH prevented the stimulatory effect of these agents. Concomitant addition of arachidonic acid did not overcome the effect of these inhibitors.Administration of hCG or incubation with LH did not elevate endogenous ovarian free arachidonate, while PGE production was enhanced. Dexamethasone prevented this stimulatory effect of hCG.Collectively, the results suggest that stimulation of ovarian PGE production by cyclic mucleotides and LH is dependent on synthesis of one more components of the PG synthetase systme rather than on substrate availability. Cyclic nucleotides may mediate the stimulatory effect of gonadotropins on PGE production 相似文献
9.
OKY-1581 is an effective inhibitor of thromboxane synthesis and . The generation of thromboxane B2 (TxB2), prostaglandin E (PGE) and prostaglandin F (PGF) was measured following clotting and during platelet aggregation induced by collagen. The presence of OKY 1581 either or caused a reduction in TxB2 generation during clotting and platelet aggregation with a concomitant increase in PGE and PGF. The effect could be observed two hours after oral or subcutaneous administration of 5 to 100 mg per rabbit and lasted for 24 to 48 hours. The reduction in TxB2 was not accompanied by an inhibition of clotting or platelet aggregation. OKY-1581 appears to be a suitable agent for studying the role of TxB2 in atherosclerosis. 相似文献
10.
H.O.J. Collier Alison A. Francis Wendy J. McDonald-Gibson S.A. Saeed 《Prostaglandins & other lipid mediators》1976,11(2):219-225
Sulphasalazine (SZ) inhibits prostaglandin (PG) biosynthesis with a potency comparable to that of aceylsalicylate. The metabolites of SZ, sulphapyridine and 5-aminosalicylic acid, were of considerably lower potency as inhibitors of PG biosynthesis in the synthetase preparations used. The inhibition of prostaglandin production by SZ could at least partly account for the clinical utility of sulphasalazine in ulcerative colitis. Sulphapyridine may help to maintain inhibitory concentrations of SZ by restraining bacterial breakdown of the active drug. 相似文献
11.
C.W. Karpen A.J. Merola R.W. Trewyn D.G. Cornwell R.V. Panganamala 《Prostaglandins & other lipid mediators》1981,22(4):651-661
Platelets from vitamin E-deficient and vitamin E-supplemented rats generate the same amount fo thromboxane A2 (TxA2) when they are incubated with unesterified arachidonic acid. Platelets from vitamin E-deficient rats produce more TxA2 than platelets from vitamin E-supplemented rats when the platelets are challenged with collagen. Arterial tissue from vitamin E-deficient rats generates less prostacyclin (PGI2) than arterial tissue from vitamin E-supplemented rats. The vitamin E effect with arterial tissue is observed when the tissue is incubated with and without added unesterified arachidonic acid. These data show that arterial prostacyclin synthesis is diminished in vitamin E-deficient rats. Vitamin E, , inhibits platelet aggregation both by lowering platelet TxA2 and by raising arterial PGI2. 相似文献
12.
R.R. Gorman R.A. Johnson C.H. Spilman J.W. Aiken 《Prostaglandins & other lipid mediators》1983,26(2):325-342
This report outlines the activity of a new thromboxane synthase inhibitor sodium, 5-(3-pyridinymethyl)-2-benzofurancarboxylate, (U-63557A). U-63557A is a potent inhibitor of the thromboxane synthase in human platelets , as well as in rhesus monkey platelets . A single oral dose of 3.0 mg/kg U-63557A inhibits the platelet thromboxane synthase in rhesus monkeys approximately 80% for at least 12 hrs. U-63557A has been administered to monkeys twice a day, (10 mg/kg) for 14 days, without evidence of drug tachyphylaxis or rebound. U-63557A does not inhibit thrombin-stimulated PGI2 biosynthesis in human endothelial cells, the 5-lipoxygenase in human neutrophils, or the cyclo-oxygenase in a variety of test systems. In anesthetized dogs, U-63557A injected i.v. at 0.1 at 5 mg/kg prevented the blockage of stenosed coronary arteries caused platelet aggregation,. Similar effects were obtained by oral administration of 1–5 mg/kg. The thromboxane synthase inhibitor was more efficacious than cyclooxgenase inhibitors and equal to PGI2 in efficacy. Under appropriate conditions the protective effects of U-63557A could be reversed by i.v. cylooxygenase inhibitors suggesting that its efficacy dependened in part of endogenous PGI2 formation. Due to its specificity, oral activity, and extended duration of action, U-63557A is a promising compound for the evaluation of the role of thromboxane synthase in a variety of patho[hysiological states. 相似文献
13.
Aubrey R. Morrison Fergus Thornton Alan Blumberg E.Darracott Vaughan 《Prostaglandins & other lipid mediators》1981,21(3):471-481
Human cortical hydronephrotic microsomes converted [14C] arachidonic acid to [14C] thromboxane B2 as the major metabolic product. Using [14C] PGH2 as substrate, similar enzymatic conversions were noted with HHT>TXB26KPGF1αPGE2PGF2α as the major products. Inhibition of thromboxane synthetase with imidazole 5 mM reduced thromboxane B2 production by 60% and the major product then was 6 keto PGF1α. After addition of imidazole, the metabolic profile showed 6KPGF1αPGE2HHT>PGF2α. Control experiments were carried out using normal cortical tissue obtained from kidneys removed surgically for carcinoma of kidney and rejected for transplantation secondary to fracture as a consequence of blunt trauma. These control kidneys, while they demonstrated an ability to generate thromboxane B2, had much less activity than hydronephrotic kidneys and with PGH2 as substrate PGE2TxB2. In addition, inhibition with imidazole produced mainly PGE2. Thus, like the rabbit and rat, there is enhanced thromboxane and prostacyclin synthesis in human ureteral obstruction and are, therefore, potential vasoactive compounds which may in part be responsible for the hemodynamic alterations occurring in human obstructive uropathy. 相似文献
14.
The evidence for the suggested roles of cyclic nucleotides as regulators of cellular proliferation in normal, transformed and neoplastic cells is reviewed. It is concluded that cyclic nucleotides are not universal regulators of cellular proliferation or . The evidence which points to the involvement of cyclic nucleotides in the regulation of other aspects of cellular metabolism in neoplastic cells is presented. Finally, the implications of the experimental evidence for the clinical aspects of cancer is discussed. 相似文献
15.
F.F. Kadlubar C.B. Frederick C.C. Weis T.V. Zenser 《Biochemical and biophysical research communications》1982,108(1):253-258
The arachidonic acid-dependent metabolism of the carcinogens, 2-naphthylamine, 4-aminobiphenyl, 2-aminofluorene, benzidine, and N-methyl-4-aminoazobenzene was mediated by a prostaglandin endoperoxide synthetase preparation. Phenacetin, a suspected carcinogen, was not a substrate but its deacetylated metabolite, -phenetidine, was rapidly oxidized. For each arylamine, extensive metabolism (14–81%) was observed, resulting in high levels of products bound covalently to protein. A low level of binding to added DNA was also detected for each substrate, except -phenetidine and N-methyl-4-aminoazobenzene. Chromatography of the ethyl acetate-extractable metabolites indicated that the major products were N-oxidized and/or C-oxidized derivatives. 相似文献
16.
Michèle Fanica-Gaignier Jenny Clément-Métral 《Biochemical and biophysical research communications》1973,55(3):610-615
Both species of δ-aminolevulinic acid (ALA) synthetase appear compartmentalized in Y. The ALA synthetase, “FI”, activity is correlated with dark respiratory metabolism and is a cytoplasmic “soluble” enzyme. The other enzyme, “FII”, induced only in light, is in chromatophores and its activity is correlated with photometabolism. 相似文献
17.
George L. Sharpe K. Sune Larsson Bertil Thalme 《Prostaglandins & other lipid mediators》1975,9(4):585-596
Administration of prostaglandin synthetase inhibitors to pregnant does and dams in late gestation was followed by contraction of the fetal ductus arteriosus when studied by the whole-body freezing method. In the rat this contraction was well established within 6 h and persisted up to 36 h following 15 mg/kg indomethacin p.o. No effect was observed in the 18 d rat fetus but fetuses at 20 d and 22 d of gestation responded significantly to indomethacin. Doses of indomethacin approaching clinical usage (2.5 mg/kg) also caused a positive response . The rat was found to be sensitive also to sodium salicylate and in the rabbit both indomethacin and sodium salicylate were effective. Exposure to prostaglandin synthetase inhibitors with resulting contraction of the ductus may seriously disturb cardiac function in the fetus. 相似文献
18.
M S Dickens J Lucas-Leonard J S Roth 《Biochemical and biophysical research communications》1975,67(4):1319-1325
The induction of TMP synthetase activity in Tetrahymena pyriformis depended upon growth conditions. Enzymatic activity was low in cells grown in complex medium, and was high in cells grown in, or shifted to, defined medium. TMP synthetase activity rose 5 hours after the shift from complex to defined medium using uracil as the pyrimidine source. The time of induction was decreased to hours using dUMP as the pyrimidine source. cGMP or its dibutyryl derivative, but not cAMP, caused the induction of TMP synthetase activity in cells grown in complex medium. Caffeine, but not theophylline, mimicked the cGMP response. cAMP decreased both the cGMP and caffeine mediated increases in TMP synthetase activity. This is the first demonstration of an effect of cGMP on induction of an enzyme of pyrimidine metabolism in any cellular system. 相似文献
19.
Rat ventral prostate spermine synthetase was inhibited by 5′-methylthioadenosine and by S-adenosylhomocysteine at concentrations which did not inhibit spermidine synthetase from the same tissue. S-Adenosylethionine inhibited both enzymes to an equal extent. These aminopropyltransferases were also inhibited by diamines not normally present in mammalian cells. All the α,ω-diamines with 3 to 12 C atoms had inhibitory activity, but 1,3-diaminopropane and 1,5-diaminopentane were most active. Spermine synthetase was more sensitive than spermidine synthetase to the effects of these diamines. These results suggest that the relative rates of spermidine and spermine formation , might be affected by the intracellular concentration of nucleosides such as S-adenosylhomocysteine. They also raise the possibility that these rates of synthesis could be selectively affected by administration of one or the other of these inhibitors. 相似文献
20.
C M Nepokroeff A A Qureshi J W Porter 《Biochemical and biophysical research communications》1975,67(1):345-352
Pigeon liver fatty acid synthetase proteins (apo- and holo-forms) have been synthesized in a cell-free system reconstituted from polysomes and a soluble enzyme fraction. Identification of the cell-free synthesized products as fatty acid synthetase was achieved by affinity chromatography, by immuno-precipitation and by the simultaneous conversion of both the authentic carrier protein and the synthesized products from the holo- to the apo-form of the synthetase. The reverse conversion was also effected. 相似文献