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1.
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
2.
Comparative metabolic conversion of aflatoxin B1 to M1 and Q1 by monkey, rat and chicken liver 总被引:1,自引:0,他引:1
We studied the metabolish of flatoxin B1 by liver microsomal preparations from monkey, rat and chicken. With all these species, both the previously recognized metabolite aflatoxin M1 as well as the newly identified aflatoxin Q1 were produced from the aflatoxin B1 substrate. Aflatoxin Q1 is an isomer of aflatoxin M1 (with the hydroxyl on the carbon β to the carbonyl of the cyclopentenone ring) which we discovered recently in rat and monkey liver incubations with aflatoxin B1. In our incubations we did not detect aflatoxin P1 which has been reported as a major metabolite of aflatoxin B1 in the monkey.In general the conversion to aflatoxin M1 was comparable among the different species (1–3% of the substrate) except in the chicken in which it was lower (0.1–0.3%). Also the conversion to Q1 was comparable to or slightly higher than the conversion to M1 with rat and chicken liver but the conversion to Q1 with the monkey liver was outstandingly high, accounting for 19–52% of the substrate in three species of monkeys tested. 相似文献
3.
The metabolism of prostacyclin (PGI2) 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-PGF1α, 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-PGF1α indicated that the monkey was not able to metabolize PGI2 as avidly as the rat. 相似文献
4.
Thromboxane B2 (TxB2) was biosynthesized from prostaglandin endoperoxides (PGG2, PGH2) using guinea pig lung microsomes and infused into an unanesthetized monkey. Urine was collected and TxB2 metabolites were isolated by reversed phase partition chromatography and high performance liquid chromatography. A major metabolite (TxB2-M) was found to be excreted in greater than two-fold abundance relative to other metabolites. Its structure was determined by gas chromatography-mass spectrometry to be dinor-thromboxane B2. In vitro incubation of TxB2 with rat liver mitochondria yielded a C18 derivative with a mass spectrum identical to that of TxB2-M, substantiating that the major urinary metabolite of TxB2 in the monkey is a product of a single step of beta-oxidation. 相似文献
5.
T.K. Gray F.W. Maddux G.E. Lester M.E. Williams 《Biochemical and biophysical research communications》1982,109(3):723-729
Rodent macrophages metabolized 25-hydroxyvitamin D3 to an unidentified metabolite during incubations. The production of this macrophage-derived metabolite of 25-hydroxyvitamin D3 increased as the substrate concentration was raised. A two step high pressure liquid chromatography system revealed a unique elution position of this macrophage-derived metabolite that did not match the elution positions of any of the vitamin D3 metabolites available in this laboratory. This unique metabolite was formed within one minute by incubated macrophages although its formation increased gradually up to 60 minutes of incubation. 相似文献
6.
Elizabeth M.K. Leovey Niels H. Andersen Pamela Bissonette 《Prostaglandins & other lipid mediators》1979,17(1):19-37
, originally introduced as an inadvertent contaminant in solutions used for evaluating the stability of prostaglandins, proved to lead to the rapid disappearance of the cyclopentenone unit of PGA2 (as monitored by circular dichroic spectroscopy). The cyclopentenone unit is converted, in various metabolites, to a 9-keto, 9α or 9β-hydroxy group lacking the ring unsaturation. The major EtoAc-soluble 9-hydroxy metabolite (Compound-I) was shown to be 9α, 15α-dihydroxy-2,3,4,5-tetranor-13--prostenoic acid. Similar tetranor 9-hydroxy metabolites with one additional degree of unsaturation, and with a 9β-hydroxy group, also occur but these have not been fully characterized. Only two of the wide range of 9-keto metabolites are fully characterized by mass spectral (MS) data: 9,15-oxo-2,3,4,5-tetranorprostanoic acid and 9,15-oxo-2,3,4,5-tetranor-13--prostenoic acid. The water soluble metabolites have not been characterized further.The fully characterized metabolites together with MS data from mixtures of minor metabolites indicate that can perform the following transformations: β-oxidation, dehydrogenation at C-15, reduction of the enone carbon-carbon double bonds (both Δ10,11 and Δ13,14), reduction of the 9-ketone, and possibly migration of the cyclopentyl double bond (Δ10,11 → Δ11,12). metabolizes 15-epimeric PGA2 equally readily with the production of similar products. PGA1 affords less 9-keto metabolites with compound I constituting 33% of the product by HPLC analysis. displays some enantioselectivity, PGA2 and 15-epi-PGA2 are each metabolized more rapidly than their enantiomers. Other prostaglandins appear to be less readily metabolized. 相似文献
7.
The urinary levels of 2,3-dinor-6-oxo-PGF1α (PGI2-M), a major metabolite of PGI2, are determined by the balance between the amount of PGI2 synthesized and the extent of its further metabolic oxidation. The purpose of the present study was to determine if the urinary excretion of PGI2-M can be used as a reliable index of the production of PGI2 in both normal Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). This involved the exclusion of differences in metabolism between these two strains of rats. In order to do so, we monitored the urinary excretion of PGI2-M during paired intravenous infusions of 6-oxo-PGF1α (the stable product of the spontaneous hydrolysis of PGI2) in conscious, unrestrained SHR and WKY rats aged 12–15 weeks, in doses ranging from 250 to 700 ng. In one experiment, PGI2 was infused instead of 6-oxo-PGF1α.The results of these experiments indicate that SHR and WKY rats are equal with regard to the transformation of 6-oxo-PGF1α and PGI2 into PGI2-M. For both groups, there is a good correlation between the amount of 6-oxo-PGF1α infused and the amount of PGI2-M excreted in urine. These observations confirm the validity of using the urinary levels of 2,3-dinor-6-oxo-PGF1α as an index of PGI2 production in both WKY and SHR. In addition, they support the conclusions drawn from our previous studies, namely that SHR do not produce more PGI2 than WKY rats , contrary to the situation prevailing . 相似文献
8.
R E Catalán M P Castillón V G Corces C Avila 《Biochemical and biophysical research communications》1977,74(1):279-284
The cytochrome P-450 content of primary hepatocyte cultures was maintained at levels close to those found by using a defined medium containing testosterone, thyroxine, hydrocortisone, estradiol, glucagon, insulin, linoleic acid and oleic acid. Using these cultures, [14C]aflatoxin B1, a potent liver carcinogen, was metabolized primarily to water-soluble metabolites. In agreement with results, aflatoxin M1 was the only nonpolar metabolite detected. In addition, a significant portion of radioactivity was covalently bound to cell constituents. These results suggest that primary hepatocyte cultures may be a good model of the liver for studying the metabolism and mechanism of action of toxic chemicals. 相似文献
9.
Metabolism of prostaglandin A. I. The kidney cortex as a major site of PGA2 degradation 总被引:2,自引:0,他引:2
The antihypertensive and natriuretic prostaglandin A2 (medullin) has been isolated and identified in rabbit renal papilla. Since PGA2, unlike prostaglandin F2 (PGE2) and prostaglandin F2α (PGF2α), is not metabolized by the lung, studies were undertaken to determine if the site of PGA2 metabolism is in the renal cortex where its primary vasodilatory and natriuretic effects occur. In experiments, homogenates of renal cortex and outer medulla were incubated with 3H-PGA2 (0.2 μc, 20 μg) at 37°C for 30 minutes. A metabolite(s) less polar than 3H-PGA2 was observed following silicic acid chromatography of acidic lipid extracts of cortical, but not outer medullary homogenates. In studies, 3H-PGA2 (2 μc, 50 μg) was injected into the renal artery of the rabbit and blood withdrawn from the ipsilateral renal vein. At least three less polar major metabolites of PGA2 were observed in the plasma within 15 seconds following injection. No appreciable 3H-PGA2 was observed in venous plasma 30 seconds following injection of 3H-PGA2. In contrast to plasma, the major urinary metabolites were more polar than PGA2. The present study reveals that PGA2 is almost completely metabolized in a single passage through the rabbit kidney suggesting this organ is a major site of PGA2 metabolism. 相似文献
10.
Göran Hansson 《Prostaglandins & other lipid mediators》1979,18(5):745-771
The metabolism of the prostaglandin F2α analogues, 15-methyl-Δ4--PGF1α and 16,16-dimethyl-Δ4--PGF1α, has been investigated in the cynomolgus monkey and the human female. The two analogues, tritium labelled in the 9β-position, were administered by intramuscular injections into the monkeys and by subcutaneous injections into the human. Excretion of tritium labelled products were followed in urine (in both species) and feces (in monkeys only) and several metabolites were identified by GC/MS. The analogues were found to be resistant to the 15-hydroxy dehydrogenase and furthermore the degradation by β-oxidation was delayed. About 13% of the given dose of 15-methyl-Δ4--PGF1α was excreted unchanged into urine and feces from the monkey. The corresponding figure for 16,16-dimethyl-Δ4--PGF1α was about 20%. In addition, a large part of the metabolites had the carbon skeleton intact and were only metabolized by ω-oxidation. The relative resistance to degradation of these two analogues is likely to be the basis for their prolonged pharmacological activity. 相似文献
11.
Sven Hammarström Kerstin Bernström Lars Örning Sven-Erik Dahlén Per Hedqvist Göran Smedegård Björn Revenäs 《Biochemical and biophysical research communications》1981,101(4):1109-1115
[5,6,8,9,11,12-3H6] Leukotriene C3 (5 μCi) was injected through a catheter into the right atrium of an anesthetized male monkey. Blood samples were drawn from the aorta via a second catheter. The concentration of tritium in blood decreased from 100 nCi/ml after 5 sec to 1 nCi/ml 15 min after injection, suggesting that leukotriene C3 was rapidly eliminated from the circulation. Chromatographic analyses of radioactive material in blood collected before recirculation had occurred (15 sec after injection) demonstrated that 40% of the radioactive material had been converted into two less polar metabolites. These products had the same chromatographic properties as leukotrienes D3 and E3, respectively. The results indicate that leukotriene C3 is rapidly transformed by monkey lung . Two minutes after injection, the component corresponding to leukotriene E3 was the predominating metabolite in blood. 相似文献
12.
Estrone glucosiduronate, 17β-estradiol-3-glucoslduronate, 17β-estradiol-17-glucosiduronate and estriol-16α-glucoslduronate have been biosynthesized in substantial yield by incubation of radioactive estrone, 17β-estradiol, estriol and uridlne diphosphoglucosiduronic acid with rhesus monkey liver homogenates. The metabolites were characterized by chromatography on Celite and DEAE-Sephadex, enzyme hydrolysis, derivative formation and crystallization to constant specific activity. The percent conversion to 17β-estradiol-17-glucosiduronate from 17β-estradlol ranged between 56–71%; from estrone, the conversion was 49–54%. Other metabolites formed from estradiol were estrone glucosiduronate(12–21%) and 17β-estradiol-3-glucosiduronate(5–12%). The same metabolites derived from estrone accounted for 18–28% and 10–14% respectively. After estriol incubation, more than 90% of the steroid was converted to estriol-16α-glucosiduronate with no detectable estriol-3-glucosiduronate. This report represents the first time that 17β-estradiol-17-glucosiduronate has been reported as a metabolite in the rhesus monkey and this is the only known species which forms 17β-estradiol-17-glucosiduronate as the predominant metabolite of either estrone or estradiol .Rhesus monkey liver is similar to the human and baboon in that it metabolizes estriol exclusively to estriol-16-glucosiduronate. 相似文献
13.
Three calcium-binding ligands in the cytosol of rat small intestine have been separated using Sephadex G-75 column chromatography. The estimated molecular weights of these ligands were 85,000, 10,000, and 800, respectively. The two high-molecular-weight ligands were found only in young rats, while the low-molecular-weight calcium-binding ligand was found in all age groups and appeared to be a calcium-bound prostaglandin metabolite. Oral administration of arachidonic acid increased and PGE2 decreased calcium absorption, while PGF2 administration showed no discernible effect on this parameter. These results suggest that the intestinal calcium transport mechanism may be modulated by prostaglandins and related metabolites. 相似文献
14.
The and metabolism of 1,2- 3H-progesterone was studied in estrogen-stimulated and control vaginae of ovariectomized mice. Employing two-dimensional thin-layer chromatography, gas-liquid chromatography and metabolite “trapping” techniques, the major and minor pathways for progesterone metabolism were determined and shown to involve saturation of the Δ4-double bond to yield 5α-pregnane compounds and reduction of the C20 and C3 ketone groups to form 20α- and 3α- and 3β-hydroxy derivatives, respectively. The quantities of 20β-hydroxy metabolites and 5β-epimers that were detected were considered not to be significant. The major metabolites formed by untreated tissues following incubation in the presence of both high (10?6M) and low (10?8M) progesterone concentrations were 3α-hydroxy-5α-pregnan-20-one and 5α-pregnane-3,20-dione. Although these two derivatives were also found in sizable quantities in estrogen-treated tissues, a marked increase (5-fold) in the rate of C20 ketone reduction at high progesterone concentrations (10?6M) to yield 20α-hydroxy-4-pregnen-3-one was demonstrated. Following intravaginal administration of 3H-progesterone , only progesterone and 3α-hydroxy-5α-pregnan-20-one were retained in appreciable quantities through 2 hr, suggesting rapid loss of 20α-hydroxy-4-pregnen-3-one and the 5α-pregnanediols from this tissue under conditions. 相似文献
15.
(1) The chemotactic activities of thromboxane B2 (TxB2, PGE2, PGF2α, the 15-oxo, 15-oxo-13,14-dihydro and 13,14-dihydro metabolites of PGE2, PGF2α, and a metabolite of TxB2 for polymorphonuclear leucocytes (PMN) have been investigated.(2) Thromboxane B2 increased the directional migrationm of rat peritoneal PMN at a concentration of 2.0 μg/ml and of human peripheral neutrophils at a concentration of 0.5 μg/ml.(3) Neither PGE2, PGF2α nor their metabolites showed chemotactic activity for rat peritoneal PMN.(4) PGF2α and 15-oxo-13,14-dihydro-thromboxane B2 showed no chemotactic activity for human peripheral PMN.(5) The possible role of thromboxane B2 in inflammation is discussed. 相似文献
16.
Penile intromissions have been thought to be the primary stimulus for reflex ovulation in light-induced persistent estrus (LLPE) rats, even though other stimuli also trigger reflex ovulation. To clarify the nature of these noncoital stimuli, intact (nonadrenalectomized) LLPE rats were briefly exposed to a variety of environmental stimuli, other than intromissions, and checked for ova 19–22 hr later. Summary of results (number of rats ovulating/number of rats tested): (A1) home cage (); (B1) home cage + vaginal taping (); (C1) home cage + male-soiled bedding (); (D1) novel cage (); (E1) novel cage + vaginal taping (); (F1) novel cage + vaginal taping + male-soiled bedding (); (G1) novel cage + vaginal taping + male-soiled bedding + male mounts without intromissions (). The percentage of LLPE rats that ovulated in the last-mentioned test condition was related to the degree of proceptivity/receptivity of the LLPE females. Eight of eight proceptive LLPE females ovulated, but only nonproceptive females ovulated. To account for reflex ovulation in the absence of intromission it has been suggested that adrenal progesterone (P) stimulates release of an ovulatory quota of luteinizing hormone. This study demonstrates no significant differences in percentage of LLPE females ovulating in corresponding groups of adrenalectomized (ADX) and adrenal-intact females. Summary of results: A2 = , B2 = , C2 = , D2 = , E2 = , F2 = , G2 = . Conclusion: (a) Exposure to a factor in male-soiled bedding induces reflex ovulation in a significant proportion of adrenal-intact LLPE animals while exposure to a novel cage and/or vaginal taping does not, (b) penile intromissions are not the primary stimulus for reflex ovulation in intact proceptive LLPE rats, and (c) adrenal P is not required for reflex ovulation after tests with noncoital stimuli. 相似文献
17.
Evidence is presented which shows that 1-(2-chloroethyl) -3-cyclohexyl-1-nitrosourea (CCNU) upon degradation provides a 2-chloroethyl alkylating intermediate, possibly 2-chloroethyl carbonium ion, and 2-chloroethanol. Thiol alkylation occurs and a major urinary metabolite of CCNU is thiodiacetic acid. A rapid microsomal hydroxylation of the cyclohexyl ring occurs which yields varying ratios of at least five metabolites: cis or trans 2-hydroxy, trans- 3-hydroxy, cis-3-hydroxy, cis-4-hydroxy and trans-4- hydroxy-CCNU. carbamoylation appears to not be due to cyclohexylisocyanate but to the various hydroxy-cyclohexylisocyanates which are formed from hydroxy CCNU metabolites. 相似文献
18.
Microbial transformation experiments were conducted with the antitumor lactone withaferin-A. NRRL 1393 transformed withaferin-A () to 15β-hydroxywithaferin-A () and 12β-hydroxywithaferin-A (). The hydroxylated metabolites were isolated by solvent extraction and were purified by column and thin-layer chromatography. Structures of the hydroxylated metabolites were determined by protonand carbon-13 NMR, IR and mass spectral analyses, and by the preparation of acylated derivatives. Compounds and inhibited the growth and biochemical functions of grown P-388 lymphocytic leukemic cells. 相似文献
19.
Mary A. Napier Irving H. Goldberg Otto D. Hensens Ray S. Dewey Jerrold M. Liesch Georg Albers-Schönberg 《Biochemical and biophysical research communications》1981,100(4):1703-1712
On the basis of spectroscopic evidence, opening of a five-membered cyclic carbonate ring (1,3-dioxolan-2-one) in the C15-subunit of the previously determined partial structure (Fig. 1) of the major neocarzinostatin chromophore (NCS-Chrom ), is proposed to account for its base-catalyzed methanolysis to NCS-Chrom . NCS-Chrom , apparently an authentic natural product present as a minor component in all preparations of NCS studied, was found to be formally equivalent to the hydrolysis/decarboxylation product of the cyclic carbonate functionality in NCS-Chrom . The mercaptan-dependent DNA strand-scission activity, equivalent for NCS-Chrom , and , is independent of the integrity of the cyclic carbonate ring system and implicates a secondary site in the C15-substructure for mercaptan activation. 相似文献
20.
Microsome-mediated metabolic activation of aflatoxin B1 (AFB1) and benzo[a]-pyrene (BP), as determined by the formation of DNA binding metabolites, was studied, using hepatic microsomes from untreated, phenobarbital (PB)-treated and 3-methylcholanthrene (MC)-treated male rats. Contrasting results were obtained for the two substrates: in the case of AFB1, microsomes from PB-treated rats were twice as active as microsomes from untreated and MC-treated rats, whereas, in the case of BP, microsomes from MC-treated rats were several fold more active than microsomes from untreated and PB-treated rats. These data strongly suggests enzyme multiplicity of microsomal mixed function oxygenase for the activation of carcinogens, especially AFB1 and BP whose reactive metabolites are believed to be epoxides. 相似文献