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1.
Studies were carried out to compare the effects of several physiological variables on adrenal microsomal drug (ethylmorphine demethylation) and steroid (21-hydroxylation) metabolism in guinea pigs. The rate of adrenal ethylmorphine (EM) metabolism increased with maturation in males but not females, resulting in a sex difference (M > F) in adrenal enzyme activity in adult guinea pigs. Twenty-one hydroxylase activity, in contrast, was similar in adrenals from males and females. The concentration of adrenal microsomal cytochrome P-450 was unaffected by age or sex. ACTH administration decreased adrenal EM demethylase activity but did not affect 21-hydroxylation. Testosterone, when given to female guinea pigs, increased the rate of EM metabolism and decreased 21-hydroxylase activity. Various compounds known to interact with adrenal microsomal cytochrome P-450 had divergent effects on EM metabolism and 21-hydroxylation . Prostaglandins E1 and F2α, spironolactone, and canrenone inhibited EM demethylation but not 21-hydroxylation. Simple aromatic hydrocarbons (benzene, toluene), in contrast, inhibited 21-hydroxylation but did not affect EM metabolism. The results indicate that adrenal drug and steroid metabolism are independently regulated and that different terminal oxidases (cytochrome P-450) are probably involved in adrenal 21-hydroxylation and EM demethylation. 相似文献
2.
Robert L. Barbieri Rapin Osathanondh Jacob A. Canick Robert J. Stillman Kenneth J. Ryan 《Steroids》1980,35(3):251-263
The effects of danazol on steroidogenesis in the 16–20 week old human fetal adrenal were examined by studying: 1) danazol binding to adrenal microsomal and mitochondrial cytochrome P-450, and 2) enzyme kinetics of danazol inhibition of the adrenal microsomal 21-hydroxylase and the mitochondrial llβ-hydroxylase. The addition of danazol to preparations of adrenal microsomes or mitochondria elicited a type I cytochrome P-450 binding spectrum. Danazol bound to microsomal cytochrome P-450 with a high affinity apparent spectral dissociation constant (Kg) of 1 μM and with a lower affinity K's of 10 μM. Danazol bound to mitochondrial cytochrome P-450 with a Kg of 5 μM. In addition, danazol competitively inhibited the microsomal 21-hydroxylase (apparent enzymatic inhibition constant KI = 0.8 μM) and the mitochondrial 11β-hydroxylase (KI = 3 μM). These findings demonstrate that low concentrations of danazol directly inhibit steroidogenesis in the human fetal adrenal . 相似文献
3.
PGE1 and PGE2 significantly increased human adrenal cAMP levels ; cortisol output was also increased in a dose related fashion. In contrast, PGF1a and PGF2a depressed adrenal cAMP (except PGF2a at 100 μg/ml). PGF1a and PGF2a depressed cortisol levels at all doses. Indomethacin or 7-oxa-13-prostynoic acid did not affect these parameters. However, when applied in conjunction with ACTH they inhibited or enhanced hormonal action depending upon the temporal sequence of application. The findings indicate that prostaglandins modulate ACTH-adrenocortical cell interaction bidirectionally, initially potentiating and subsequently depressing ACTH stimulated events. 相似文献
4.
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
5.
A series of analogues of dopamine (DA) with varying degrees of conformational flexibility have been examined as potential substrates or competitive inhibitors of the enzyme norepinephrine N-methyltransferase (NMT). A conformationally defined (rigid) analogue of the fully extended conformation of DA, 2-amino-6, 7-dihydroxybenzonorbornene hydrobromide (; 6, 7-D2HX) proved to be a better substrate than the non-catechol parent 2-aminobenzonorbornene (; 2HX). However, analogues and displayed equivalent competitive inhibitory activity toward phenylethanolamine (PEA). Neither 6, 7-ADTN (5), a DA analogue in the 2-aminotetralin (2AT) system, nor 6, 7-DTHIQ (), a DA analogue in the tetrahydroisoquinoline (THIQ) system, showed substrate activity; 6, 7-ADTN was a poorer competitive inhibitor than the parent 2AT but 6, 7-DTHIQ was a better competitive inhibitor than its parent, THIQ (). A tricyclic conformationally defined analogue of 6, 7-ADTN was devoid of either substrate or inhibitory activity. From these results it may be concluded that a fully extended side chain conformation is required for NMT substrate activity, and the better substrate activity for 6, 7-D2HX compared to is consistent with a proper catechol orientation for interaction with the norepinephrine (NE) binding site of NMT. 相似文献
6.
Cytoplasmic free and bound polysomes were isolated from bovine adrenal cortex, and used to program protein synthesis in rat liver cell sap and wheat germ lysate systems. Synthesis of adrenodoxin(Ad) and adrenodoxin reductase(AdR) in the cell-free systems was determined by immunoprecipitation using monospecific antibodies, and the sizes of the products were analyzed by SDS-polyacrylamide gel electrophoresis. Ad was synthesized by both free and bound polysomes as a putative large precursor having molecular weight of approximately 20,000 daltons, which was processed to mature size Ad (MW 12,000 daltons) by incubation with adrenal cortex mitochondria. On the other hand, AdR was synthesized only by free polysomes apparently as the mature size product. 相似文献
7.
Because certain inhibitors of norepinephrine N-methyltransferase (NMT, the epinephrine-forming enzyme) are α2 adrenoreceptor blockers, we compared the ability of various compounds to inhibit rat brain NMT activity and the binding of tritiated clonidine to rat brain membranes . There was no correlation between potency of NMT inhibition and potency of α2 receptor antagonism (as measured by inhibition of tritiated clonidine binding) among NMT inhibitors representing several chemical classes or among members of a single class of compounds, l-aminoindans. In addition, several potent α2 blocking drugs were essentially inactive as NMT inhibitors. These findings indicate that NMT inhibition and α2 blockade are dissociable activities. Future development of NMT inhibitors should include this dissociation as a goal to increase the usefulness of NMT inhibitors as pharmacologic tools. 相似文献
8.
R W Fuller H D Snoddy K W Perry B W Roush B B Molloy F P Bymaster D T Wong 《Life sciences》1976,18(9):925-933
Quipazine, 2-(1-piperazinyl)-quinoline, is a drug that has been reported to stimulate serotonin receptors in brain. We therefore studied the effect of quipazine on several parameters of serotonin metabolism in rat brain. Quipazine caused a slight, dose-related elevation of serotonin levels and decrease in 5-hydroxyindoleacetic acid levels for 2–4 hrs after it was administered. The decrease in 5-hydroxyindoleacetic acid levels was probably due primarily to a depression of 5-hydroxyindole synthesis, since quipazine also decreased the rate of 5-hydroxytryptophan accumulation after NSD 1015, the rate of serotonin decline after α-propyldopacetamide, and the rate of 5-hydroxyindoleacetic acid accumulation after probenecid. The elevation of serotonin was probably due to weak inhibition of monoamine oxidase. Quipazine reversibly inhibited the oxidation of serotonin by rat brain monoamine oxidase and protected against the irreversible inactivation of the enzyme . Quipazine also was a potent inhibitor of serotonin uptake into brain synaptosomes and attained concentrations in brain higher than the IC50. However, quipazine did not prevent the depletion of brain serotonin by p-chloroamphetamine . In addition to stimulating serotonin receptors in brain, quipazine may inhibit monoamine oxidase and serotonin reuptake . 相似文献
9.
Day 10 rat embryos grown showed significant retardation in growth and development when culture media contained acetaldehyde. A concentration-response range for acetaldehyde-induced embryotoxicity was defined, from no effect at 5μM to complete lethality at 100μM. The relative teratogenicity of ethanol and acetaldehyde, and the potential roles of these compounds in producing the Fetal Alcohol Syndrome are discussed.Despite intensive investigation into alcohol teratogenicity, the mechanism that produces the Fetal Alcohol Syndrome (FAS) remains unknown. Observed anomalies may result from direct embryonic exposure to ethanol or one of its metabolites, or from some indirect effect such as altered placental function or maternal nutritional status. Use of techniques allows study of direct embryonic exposures in the absence of indirect influences. Under such conditions, ethanol has been found to exert direct embryotoxicity (1). Rat embryos, grown as cultured explants and subjected to ethanol concentrations of 32.5 or 65mM, were retarded in growth and development when compared to untreated controls. In this paper, we report direct embryotoxic effects of acetaldehyde, the primary metabolite of ethanol, at concentrations as low as 25μM.Acetaldehyde teratogenicity has not been extensively studied. Veghelyi et al. (2) and Lambert, Papp and Nishiura (3) employed a combination of ethanol and disulfiram (an inhibitor of acetaldehyde-oxidizing enzymes). Teratogenic effects exceeded expectations based upon assumption of an additive interaction between these two compounds, and were attributed to elevated maternal blood acetaldehyde. O'Shea and Kauffman (4,5) and Dreosti et al. (6) administered acetaldehyde to pregnant animals by injection. Treatment resulted in retarded growth and development, decreased DNA synthesis, and increased frequencies of malformation and resorption. While these studies imply a role for acetaldehyde in alcohol-induced teratogenesis, indirect effects through altered maternal or placental factors cannot be eliminated. We present here the first concentration-response data for direct ebryonic exposure to acetaldehyde. 相似文献
10.
C Hedgcoth K Thomas K Scheets S Allen 《Biochemical and biophysical research communications》1980,95(2):880-886
When murine sarcoma virus-transformed cells are labeled with [3H]lysine for various periods, 5 of 6 isoaccepting lysine tRNAs separable by RPC-5 chromatography are aminoacylated in 1 hr to the same extent that they are aminoacylated . The sixth isoacceptor, tRNA6Lys, is not aminoacylated to a measurable extent in 1 hr, although it is present in the tRNA prepared from the cells. All six isoacceptors are aminoacylated with [3H]lysine when the labeling period is 2 or 3 hr. These results further show that correlations of the amount of tRNA4Lys with cell division accurately reflect the situation . Results of differential centrifugation indicate that tRNA6Lys occurs in mitochondria. 相似文献
11.
Effect of carbamyl phosphate on the regulation of nitrogenase in Clostridium pasteurianum 总被引:5,自引:0,他引:5
One mM carbamyl phosphate inhibited the acetylene reduction activity of nitrogenase 30% whereas at high concentrations a maximum inhibition of 50% was observed. When 1 mM carbamyl phosphate was added to a culture growing of N2 1) nitrogenase synthesis was completely repressed and 2) after a period of 2.5 hrs in the absence of growth, the specific activity decreased to less than 50% of its activity just before the addition of the inhibitor. 相似文献
12.
Vesna Ivanovic Nicholas E. Geacintov I.Bernard Weinstein 《Biochemical and biophysical research communications》1976,70(4):1172-1179
A new approach has been developed to detect ultra low concentrations of benzo(a)pyrene products bound to nucleic acids . The binding to DNA of hamster embryo cell cultures was characterized by low temperature fluorescence spectroscopy. The method can detect less than one polycyclic hydrocarbon residue per 50,000 nucleotides. The fluorescence spectra indicate that the benzo(a)pyrene derivative bound to DNA has a pyrene-like chromophore and resembles that obtained when DNA is reacted with the 7,8-diol-9,10-oxide of benzo(a)pyrene. This confirms that metabolism of the 7,8,9,10 ring on benzo(a)pyrene precedes reaction with DNA. The method should be useful for detecting and characterizing the binding of other fluorescent carcinogens to nucleic acids. 相似文献
13.
J.F. McKelvy P. LeBlanc C. Laudes S. Perrie Y. Grimm-Jorgensen C. Kordon 《Biochemical and biophysical research communications》1976,73(2):507-515
Bacitracin was found to be an effective inhibitor of the degradation of both thyrotropin releasing factor1 (TRF) and luteinizing hormone releasing factor (LRF) by guinea pig hypothalamic and whole brain homegenates and rat hypothalamic homogenates and subcellular fractions. Bacitracin was effective in inhibiting the degradation of TRF and LRF, as determined by radioimmunoassay, where it exhibited no interference with the assays. Kinetic studies of the degradation of exogenous synthetic [3H]-TRF demonstrated non-competitive inhibition by bacitracin with Ki = 1.9 × 10?5 M, while studies on the degradation of [3H] LRF indicated competitive inhibition with Ki = 1.7 × 10?5 M. Electrophoretic and amino acid analysis revealed that bacitracin itself was not degraded during the course of the incubation. 相似文献
14.
The effect of morphine sulfate (MS) on adenylate cyclase (AC) and phosphodiesterase (PDE) activities in the rat striatum was investigated. MS produced a dose-dependent increase in basal AC activity and did not alter sodium fluoride-induced stimulation both (7.5–30 mg/kg, 1 hr pretreatment, i.p.) and (1–100μM). , when submaximal effective concentrations of dopamine and MS were combined, there was an additive effect. However, administration of MS did not alter dopamine-induced stimulation of AC activity. MS, and inhibited PDE activity in a dose-dependent manner only with the high substrate concentration (3.3 × 10−3M cyclic AMP). Preliminary results from this study indicate that morphine affects the cyclic AMP system. 相似文献
15.
A.W. Ford-Hutchinson A. Rackham R. Zamboni J. Rokach S. Roy 《Prostaglandins & other lipid mediators》1983,25(1):29-37
Synthetic leukotriene B4 (LTB4) and its ω-oxidation products, 20 OH-LT4 and 20 COOH-LTB4, were tested for their ability to induce the aggregation of rat neutrophils , to contract the guinea pig parenchymal strip and to cause vascular permeability changes in rabbit skin . 20 OH-LTB4 had 10, 100 and 20% of the activity of LTB4 in the neutrophil aggregation, parenchymal strip and vascular permeability assays respectively. 20 C00H-LTB4 was inactive and showed <1% of the activity of LTB4. These results show that while ω-oxidation is a route for biological inactivation of LTB4, 20 OH-LTB4 still retains significant biological activity. 相似文献
16.
Dibutyryl cGMP: inhibitor of the effect of cholecystokinin and gastrin on the guinea pig gallbladder in vitro 总被引:1,自引:0,他引:1
P Poitras D Iacino J H Walsh 《Biochemical and biophysical research communications》1980,96(1):476-482
N2, O2-di-butyryl guanosine 3′:5′ monophosphate (Bt2 cGMP), a known competitive and selective inhibitor of the effect of cholecystokinin on the pancreatic acinar cells was tested for its effect on the guinea pig gallbladder . Bt2 cGMP inhibited competitively the contractile effect of cholecystokinin octapeptide, and also inhibited the contraction induced by sulfated gastrin-17. Bt2 cGMP failed to inhibit the contraction induced by bombesin, acetylcholine or histamine. The 8-bromo derivative of cGMP and the dibutyryl derivative of cAMP did not affect contraction stimulated by cholecystokinin octapeptide. Since it is specific for gastrincholecystokinin peptides, and not restricted to the pancreas, Bt2 cGMP could be used to recognize the action of these peptides. 相似文献
17.
18.
Makoto Fukae Gerald L. Mechanic 《Biochemical and biophysical research communications》1976,71(2):651-657
A partially cleaved α1(I) chain, α1χ, has been isolated from earlier synthesized or older (acid-extracted) guinea pig skin collagen. The α1χ component is shown to be absent from the newly synthesized (neutral salt-extracted) collagen. This degradation is a result of specific proteolytic sission of α1(I) chain since the soluble collagen has no corresponding product from the α2 chain. The proteolytic cleavage is believed to result from processes related to natural physiological maturation of collagenous tissue. 相似文献
19.
The effect of 3,3'-dimethoxybenzidine (-dianisidine) on the conversion of cholesterol to pregnenolone was investigated in a reconstituted side chain cleavage system using enzymes purified from bovine adrenal cortex; d--aminoglutethimide was also assayed under similar conditions for comparison. 3,3'-Dimethoxybenzidine was found to be a potent inhibitor of pregnenolone formation, causing 50% inhibition at a concentration of 1.5 μM when using 70 μM cholesterol — this dose is approximately one fourth that required of 3-methoxybenzidine and one twentieth that required of benzidine for equal inhibition. In the same system, d--aminoglutethimide exhibited an I50 value of about 55 μM. No effects of 3,3'-dimetoxybenzidine on adrenodoxin reductase or adrenodoxin activities could be detected, and inhibition of side chain cleavage could be relieved by dilution suggesting that the inhibitor acts by reversibly binding to cytochrome P-450scc. 相似文献
20.
Oscar Hernandez Michael Walker Richard H. Cox Gary L. Foureman Brian R. Smith John R. Bend 《Biochemical and biophysical research communications》1980,96(4):1494-1502
13C-NMR analysis of the glutathione conjugates formed from (±)-benzo(a)-pyrene 4,5-oxide-4,5-13C by a purified glytathione transferase from little skate () liver demonstrated that equivalent amounts of the positional isomers (4,5-dihydro-4-hydroxy-5-glutathionylbenzo(a)pyrene and 4,5-dihydro-4-glutathionyl-5-hydroxybenzo(a)pyrene) were formed. Separation of these conjugates by HPLC and subsequent 13C-NME studies showed that only one diastereoisomer of each positional isomer was formed by the skate enzyme, each enantiomer of the arene oxide having produced only one of the two possible positional isomers. The non-enzymic reaction of (±)-benzo(a)pyrene 4,5-oxide with glutathione produced the four possible stereoisomers resulting from addition to the epoxide ring. This was also true when rat liver cytosol was used as the source of transferase activity. The data demonstrate that skate liver glutathione transferase 4 has high substrate regiospecificity and stereospecificity for (±)-benzo(a)pyrene 4,5-oxide. 相似文献