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PubMed1994

Metabolism of tritiated D-alpha-tocopherol and D-alpha-tocopheryl succinate in intraruminally dosed sheep.

The comparative disposition (absorption, plasma disposition, tissue distribution) of D-alpha-tocopherol and of D-alpha-tocopheryl succinate (forms of vitamin E) was investigated in 10 ruminally cannulated wethers. Tritiated tocopherols (4 microCi/kg BW) were administered directly into the rumen. Plasma and ruminal fluid activity were regularly measured from the time of administration to 96 h after administration. Radioactivity in lymph was measured in four additional wethers dosed intraruminally (100 microCi) with the same tritiated compounds. Lymph was collected from the cannulated thoracic duct during the first 24 h after the administration. Wethers were killed and selected tissues were measured for their tocopherol activity. Plasma and ruminal fluid specific activity vs time were modeled using appropriate compartmental and noncompartmental approaches. It was shown that there was a large difference in the relative bioavailability of the two compounds with a four times higher (P < .05) relative availability of D-alpha-tocopherol than of D-alpha-tocopheryl succinate. This was explained in terms of incomplete hydrolysis of tocopheryl succinate before absorption. By direct ruminal fluid measurement, it was estimated that tocopherol behaves similarly to a soluble ruminal marker with a ruminal transit time of approximately 19 h. In plasma, the total mean residence time was 148 h for D-alpha-tocopherol and 106 h for D-alpha-tocopheryl succinate. The lymph activity was mainly associated with tocopherol both after tocopherol and tocopheryl succinate administration. Tissue concentration of radioactivity was higher (P < .05) for sheep dosed with tocopherol than for those dosed with the tocopheryl succinate, confirming the difference in bioavailability of the two compounds.

Animals↗
PubMed1991

Stability and compatibility of methylprednisolone sodium succinate and cimetidine hydrochloride in 5% dextrose injection.

The stability and compatibility of methylprednisolone sodium succinate in admixtures with cimetidine hydrochloride in 5% dextrose injection were determined. Admixtures containing methylprednisolone sodium succinate, in concentrations equivalent to methylprednisolone 0.4 or 1.25 mg/mL, and cimetidine 3 mg/mL (as the hydrochloride salt) were prepared in 5% dextrose injection 100 mL. Control solutions containing each drug alone at the same concentrations were also prepared. The admixtures were prepared in triplicate and were kept in polyvinyl chloride infusion containers at controlled room temperature (24 degrees C). Immediately after mixing and at 2, 4, 8, 12, and 24 hours, samples were removed and visually inspected, measured for pH, and assayed by stability-indicating high-performance liquid chromatography to determine the concentrations of methylprednisolone 21-succinate ester and cimetidine. No visual evidence of incompatibility was noted either with the unaided eye or a microscope. No substantial changes in pH occurred over the study period. The addition of cimetidine decreased the pH of the methylprednisolone sodium succinate control solutions from about 7.3 to about 5.6. The concentrations of methylprednisolone 21-succinate ester and cimetidine in both test and control solutions did not change significantly over the 24-hour study period. Methylprednisolone sodium succinate, in concentrations equivalent to methylprednisolone 0.4 and 1.25 mg/mL, was chemically stable and visually compatible in admixtures with cimetidine 3 mg/mL (as the hydrochloride salt) in 5% dextrose injection 100 mL at 24 degrees C for 24 hours.

Cimetidine↗
PubMed1986

Compatibility of aminophylline and methylprednisolone sodium succinate intravenous admixtures.

The stability of aminophylline and methylprednisolone sodium succinate in admixtures containing both drugs was studied. Admixtures containing aminophylline 1.0 mg/mL and methylprednisolone sodium succinate 2.0 and 0.5 mg/mL were prepared in both 5% dextrose injection and 0.9% sodium chloride injection. Each admixture was prepared in triplicate and samples were kept at room temperature in glass. Immediately after admixture and at one, two, and three hours, samples were visually inspected, tested for pH, filtered, and assayed in duplicate by high-performance liquid chromatography for theophylline concentration and for both methylprednisolone sodium succinate and methylprednisolone alcohol. Control solutions containing only one of the two drugs were also tested. No visual changes were observed. The admixtures had higher pH values after aminophylline was added, but pH of the samples did not change significantly. Aminophylline concentrations did not change significantly throughout the study period. In 0.9% sodium chloride admixtures with methylprednisolone sodium succinate 0.5 mg/mL, less than 90% of the initial methylprednisolone concentration remained at two hours at the 2.0 mg/mL initial concentration, less than 90% remained at three hours. However, methylprednisolone alcohol (a pharmacologically active form of methylprednisolone sodium succinate) was detected in increasing concentrations after the first hour. Aminophylline in a final concentration of 1.0 mg/mL or less can be mixed with methylprednisolone sodium succinate in a final concentration of 2.0 mg/mL or less in 5% dextrose injection or 0.9% sodium chloride injection and administered intravenously within three hours after mixing.

Aminophylline↗
PubMed1997

Distribution of succinic semialdehyde reductase in rat brain.

Succinic semialdehyde reductase (SSR) that catalyzes the reduction of succinic semialdehyde (SSA) to gamma-hydroxybutyrate (GHB) has been identified as one of the NADPH-dependent aldehyde reductases. Reduction of SSA to GHB strongly supports the proposal that GHB biosynthesis may be an important step in the GABA shunt. It is pharmacologically significant in anesthesia, evoking the state of sleep, and an increase in brain dopamine level. Monoclonal antibodies against bovine brain succinic semialdehyde reductase were produced. Using the anti-succinic semialdehyde reductase antibodies, we investigated the distribution of brain succinic semialdehyde reductase in rat brain. The brain tissues were sectioned with a basis on the rat brain atlas of Paxinos and were stained by the immunoperoxidase staining method using monoclonal antibodies. In the section of the frontal lobe, immunoreactive cells were observed in the lateral septal area, the ventral pallidum, which belongs to the substantia innominata. We could observe immunoreactive cells in the reticular thalamic nucleus, which is closely related with 'sleeping', the basal nuclei of Meynert, which is associated with Alzheimer's disease, and hypothalamic nuclei. Immunoreactive cells were also shown in raphe nuclei or the reticular formation of the midbrain, cerebellum, and inferior olivary nuclei of the medulla oblongata. Succinic semialdehyde reductase-immunoreactive cells were distributed extensively in rat brain, especially immunoreactive cells were strongly observed in the areas associated with the limbic system and reticular formation.

Animals↗
PubMed1987

Succinic acid production by Bacteroides fragilis. A potential bacterial virulence factor.

We previously demonstrated that Bacteroides species elaborate a factor that impairs polymorphonuclear leukocyte (PMN) migration. This factor, active at a pH of 5.5 but not at 7.4, had similar inhibitory characteristics as the Bacteroides metabolite succinic acid. We examined the kinetics of production of this inhibitory factor and correlated its presence with succinic acid concentrations in the culture filtrate. In the four to six hours after Bacteroides fragilis 9032 reached the stationary phase of growth, there was a large increase in succinic acid production with an accompanying reduction in culture pH. This correlated well with the generation of a leukocyte-inhibitory factor. Pure succinic acid in sterile culture medium at concentrations similar to those detected in the 18-hour culture filtrate (20 mmol/L) produced comparable reduction in PMN migration. Following gel filtration chromatography of B fragilis culture filtrate, the fractions containing succinic acid labeled with carbon 14 inhibited PMN migration.

Bacteroides↗
PubMed1996

Sodium-dependent succinate decarboxylation by a new anaerobic bacterium belonging to the genus Peptostreptococcus.

An anaerobic bacterium was isolated from a polluted sediment, with succinate and yeast extract as carbon and energy sources. The new strain was Gram-positive, the cells were coccal shaped, the mol% G+G content of the genomic DNA was 29, and the peptidoglycan was of the L-ornithine-D-glutamic acid type. Comparative sequence analysis of the 16S rRNA gene showed the new strain to belong to the genus Peptostreptococcus. Succinate, fumarate, pyruvate, 3-hydroxybutyrate and lysine supported growth. Succinate was degraded to propionate and presumably CO2, with a stoichiometric cell yield. Key enzymes of the methylmalonyl-CoA decarboxylase pathway were present. The methylmalonyl-CoA decarboxylase activity was avidin-sensitive and sodium dependent, and about 5 mM Na+ was required for maximal activity. Whole cells, however, required at least 50 mM sodium for maximal succinate decarboxylation activity and to support the maximum growth rate. Sodium-dependent energy conservation coupled to succinate decarboxylation is shown for the first time to occur in a bacterium belonging to the group of Gram-positive bacteria containing the peptostreptococci and their relatives.

Bacteria, Anaerobic↗
PubMed1997

Environmental and physiological factors affecting the succinate product ratio during carbohydrate fermentation by Actinobacillus sp. 130Z.

Actinobacillus sp. 130Z fermented glucose to the major products succinate, acetate, and formate. Ethanol was formed as a minor fermentation product. Under CO2-limiting conditions, less succinate and more ethanol were formed. The fermentation product ratio remained constant at pH values from 6.0 to 7.4. More succinate was produced when hydrogen was present in the gas phase. Actinobacillus sp. 130Z grew at the expense of fumarate and l-malate reduction, with hydrogen as an electron donor. Other substrates such as more-reduced carbohydrates (e.g., d-sorbitol) resulted in higher succinate and/or ethanol production. Actinobacillus sp. 130Z contained the key enzymes involved in the Embden-Meyerhof-Parnas and the pentose-phosphate pathways and contained high levels of phosphoenolpyruvate (PEP) carboxykinase, malate dehydrogenase, fumarase, fumarate reductase, pyruvate kinase, pyruvate formate-lyase, phosphotransacetylase, acetate kinase, malic enzyme, and oxaloacetate decarboxylase. The levels of PEP carboxykinase, malate dehydrogenase, and fumarase were significantly higher in Actinobacillus sp. 130Z than in Escherichia coli K-12 and accounted for the differences in succinate production. Key enzymes in end product formation in Actinobacillus sp. 130Z were regulated by the energy substrates.

Actinobacillus↗
PubMed1984

Asymmetry of the Na+-succinate cotransporter in rabbit renal brush-border membranes.

We have investigated the symmetry of Na+-succinate cotransport in rabbit renal brush-border membrane vesicles. Succinate influx and efflux kinetics were measured under voltage-clamped conditions using [14C]succinate and a rapid filtration procedure. Both influx and efflux were Na+-dependent, saturable, temperature-sensitive, and influenced by the trans Na+ and succinate concentrations. The system was judged to be asymmetric, since the maximal velocity for influx was 3-fold higher than that for efflux, and trans Na+ inhibited influx more than efflux. This may be due to the asymmetrical insertion of the transporter in the brush-border membrane, which leads to differences in either the forward and backward translocation rates of the fully loaded carrier or the Na+ and succinate binding constants at the inner and outer faces of the membrane.

Animals↗
PubMed1990

Lack of toxicity/carcinogenicity of monosodium succinate in F344 rats.

The toxicity/carcinogenicity of monosodium succinate, a food additive, was examined in F344 rats. The oral LD50 was greater than 8 g/kg body weight. In a 13-wk subchronic oral toxicity study, the only toxicological finding was suppression of body-weight gain in groups given greater than or equal to 2.5% monosodium succinate in the drinking-water. Histological examination revealed no toxic lesions specifically caused by the compound in any organs of any of the treated rats. The maximum tolerated dose was determined to be 2-2.5% on the basis of body-weight depression. In a long-term (2-yr) toxicity/carcinogenicity study, monosodium succinate was given ad lib. in drinking-water (distilled water) at levels of 0, 1 or 2% to groups of 50 male and 50 female rats. No toxic lesion specifically caused by long-term administration of monosodium succinate was detected. No dose-related increase was found in the incidences of tumours in any organ or tissue except for C-cell tumours of the thyroid gland of females. The incidence of these tumours in females given the 2% dose was higher than that in controls but not significantly so, and a positive trend for this tumour was noted in females. C-Cell tumour is one of the most commonly observed spontaneous tumours in ageing female rats of this strain and occurs at a variable incidence. There was no difference between the female control and treated groups in the incidence of preneoplastic change of the thyroid gland. Furthermore, the incidence of C-cell tumours in the female control group was lower than that in our historical controls. It is concluded that the increase in C-cell tumours in the female high-dose group and the detection of a positive trend for this tumour in females were probably a function of experimental variability and were not related to treatment. The results indicate that monosodium succinate had neither toxic nor carcinogenic activity in F344 rats when it was given continuously at levels of 1 or 2% in the drinking-water for 2 yr.

Animals↗
PubMed1969

Activation of liver succinate dehydrogenase in rats exposed to hypobaric conditions.

1. On brief exposure of rats to hypobaric conditions, the activity of hepatic mitochondrial succinate dehydrogenase was raised from the basal state to a ;partially activated state'. This was further raised to ;fully activated state' by preincubation of mitochondria with succinate, as was the activity in mitochondria from normal rats. 2. On washing mitochondria with the homogenizing sucrose medium the activity excess obtained on preincubation with succinate was lost in mitochondria from both normal and treated rats. 3. The enzyme in the ;partially activated state' from animals exposed to hypobaric conditions was stable to the washing procedure but was labilized and reverted to a low basal state of activity on freezing and thawing of the isolated mitochondria. 4. The results suggest that activation of succinate dehydrogenase under hypobaric conditions represents a conformational change leading to a stable, partially activated, form of the enzyme system: this is the first evidence of physiological modulation of this rate-limiting step in the control of the rate of oxidation of succinate.

Animals↗
PubMed1986

Assay of prolyl 4-hydroxylase by the chromatographic determination of [14C]succinic acid on ion-exchange minicolumns.

An assay for prolyl 4-hydroxylase (EC 1.14.11.2) is described which measures succinic acid produced during the decarboxylation of 2-oxoglutaric acid in the presence of poly(L-Pro-Gly-L-Pro). [1-14C]Succinic acid was separated from its precursor 2-oxo[5-14C]glutaric acid by using ion-exchange minicolumns. The contamination of succinic acid by 2-oxoglutaric acid was approx. 1%, and the recovery of succinic acid was 100%. Kinetic parameters of prolyl 4-hydroxylase measured by the assay showed good agreement with published values. Our experience indicates that the measurement of prolyl 4-hydroxylase by the production of succinic acid is especially suited to investigations involving large numbers of assays.

Carbon Radioisotopes↗
PubMed2006

Direct and indirect roles of cytochrome b in the mediation of superoxide generation and NO catabolism by mitochondrial succinate-cytochrome c reductase.

Mitochondrial superoxide (O2*-) production is an important mediator of oxidative cellular injury. Succinate-cytochrome c reductase (SCR) of the electron transport chain has been implicated as an essential part of the mediation of O2*- generation and an alternative target of nitric oxide (NO) in the regulation of mitochondrial respiration. The Q cycle mechanism plays a central role in controlling both events. In the present work, O2*- generation by SCR was measured with the EPR spin-trapping technique using DEPMPO (5-diethoxylphosphoryl-5-methyl-1-pyrroline N-oxide) as the spin trap. In the presence of succinate, O2*- generation from SCR was detected as the spin adduct DEPMPO/*OOH. Inhibitors of the Q(o*-) site only marginally reduced (20-30%) this O2*- production, suggesting a secondary role of Q(o*-) in the mediation of O2*- generation. Addition of cyanide significantly decreased (approximately 70%) O2*- production, indicating the involvement of the heme component. UV-visible spectral analysis revealed that oxidation of ferrocytochrome b was accompanied by cytochrome c(1) reduction, and the reaction was mediated by the formation of an O2*- intermediate, indicating a direct role for cytochrome b in O2*- generation. In the presence of NO, DEPMPO/*OOH production was progressively diminished, implying that NO interacted with SCR or trapped the O2*-. The consumption of NO by SCR was investigated by electrochemical detection using an NO electrode. In the presence of succinate, SCR-mediated NO consumption was observed and inhibited by the addition of superoxide dismutase, suggesting the involvement of O2*-. Under the conditions of argon saturation, the NO consumption rate was not enhanced by succinate, suggesting a direct role for O2*- in the mediation of NO consumption. In the presence of succinate, oxidation of the ferrocytochrome b moiety of SCR was accelerated by the addition of NO, and was inhibited by argon saturation, indicating an indirect role for cytochrome b in the mediation of NO consumption.

Animals↗
PubMed1991

[Regulation of the heart mitochondrial respiration rate. Comparison of oxidation of succinate and NAD-dependent substrates].

Regulation of respiration at all rates between State 4 and State 3 was studied in heart mitochondria oxidizing FAD- and NAD-dependent substrates (succinate, pyruvate + + malate and palmitoylcarnitine). The creatine phosphokinase ADP-regenerating system was used which allows to fix the concentrations of extramitochondrial adenine nucleotides in such a way that the rate of respiration is controlled by mitochondrial processes alone. It was shown that respiration is controlled by delta mu(H+)-utilizing system within the respiration rate interval from State 4 till 70-80% of the maximal rate in State 3 (corresponding to physiological rates) both for NAD- and FAD-dependent substrates. The main step in the control of respiration near State 4 is proton leakage through the inner mitochondrial membrane, whereas in all the other parts of the mentioned interval this role is assigned to the adenine nucleotide translocator (ANT). The control coefficient for ANT is higher, while that of proton leakage is lower at the same relative rates of respiration with NAD-dependent substrates compared with succinate. These differences were found to be related to much higher values of the membrane potential generated at the same relative rates of succinate oxidation in comparison with the case with pyruvate + + malate. The contribution of delta mu(H+)-utilizing system to respiration control sharply decreases, whereas that of the delta mu(H+)-generating system increases at maximal rates of respiration near State 3. This phenomenon in more characteristic of succinate. In this case the control coefficient of ANT drops to zero, while that of succinate dehydrogenase rises to 0.7.

Adenine Nucleotides↗
PubMed1978

The indispensability of phospholipid and ubiquinone in mitochondrial electron transfer from succinate to cytochrome c.

The indispensability of phospholipid and ubiquinone (Q) in mitochondrial electron transfer was studied by depleting phospholipid and Q in succinate-cytochrome c reductase and then replenishing the depleted enzyme. More than 90% of phospholipid and Q was removed by repeated ammonium sulfate-cholate fractionation. The depleted succinate-cytochrome c reductase showed no enzymatic activity for succinate leads to c or QH2 leads to c and yet retained most of the succinate leads to Q activity. All enzymatic activity was restored upon the addition of Q and phospholipid. Restoration required the addition of Q prior to the addition of phospholipid. Reversing the addition sequence or addition of a mixture of phospholipid and Q resulted only in a small restoration of activities. The conditions for restoration are given in detail. Removal of phospholipid from succinate-cytochrome c reductase resulted in reduction of cytochrome c1 in the absence of exogenous electron donor. Replenishing the preparation with phospholipid brought about the reoxidation of cytochrome c1 in the absence of electron acceptor or oxygen.

Animals↗
PubMedDate not supplied

[Reaction ability and alkylation kinetics of sulfhydride groups of soluble succinate dehydrogenase].

Inhibition kinetics of succinate--an acceptor of oxidoreductase activity of soluble succinate dehydrogenase by N-ethylmaleimide is studied. The alkylation reaction is described by the kinetic equation of the first order, its stechiometric coefficient being 1. The binding of enzyme sulphhydride groups by p-chloromercuriumbenzoate blocks the enzyme alkylation and its inhibition by oxaloacetate. Succinate protects succinate dehydrogenase from the inhibitory effect of N-ethylmaleimide. The reaction of the enzyme with an alkylating agent in the presence of different substrate concentrations corresponds kinetically to the model, according to which a sulphhydride group acts in the active site of the enzyme. pKa of this group is 7.0 at 20degreesC. The dependency of the maximal substrate oxidation reaction rate and that of the enzyme alkylation rate on pH coinside at the pH range 5.8--7.8. The presence of anions in the alkylation medium decreases the reaction ability of the active site with respect to N-ethylmaleimide. A mechanism of the initial stage of succinate oxidation with the cooperation of the sulphhydride group of the enzyme active site is postulated.

Binding Sites↗
PubMed1983

Kinetics of sodium succinate cotransport across renal brush-border membranes.

The kinetics of Na/succinate cotransport across renal brush-borders was studied using membrane vesicles. Initial rates of succinate uptake (Js) were estimated from 1-s uptakes measured under voltage-clamped conditions. Lowering the external (cis) sodium concentration reduced the succinate Kt without affecting the Jsmax. Increasing the intravesicular (trans) sodium concentration reduced both Jsmax and Kt. This trans inhibition by Na was relieved by trans-succinate. Varying the membrane potential from -60 to +60 reduced succinate transport in an exponential manner, which was reflected by a Kt effect, i.e. an increase in the Kt with no change in Jsmax. The membrane potential results suggest that the succinate/sodium-carrier complex bears a net positive charge. On the basis of these and earlier observations, we propose that Na/succinate cotransport across renal brush-borders is described by an Iso Ordered Quad Quad reaction kinetics in which three Na ions first bind to the carrier to increase its affinity for succinate.

Animals↗
PubMed1994

Correlation between myocardial blood flow and tissue succinate during acute ischemia.

This study was performed to clarify the relationship between degree plus duration of myocardial ischemia and tissue succinate or lactate contents, and to assess whether their accumulation might be a metabolic marker of ischemic myocardium. Regional myocardial blood flow (MBF) was measured using the hydrogen gas clearance method in anesthetized open-chest dogs subjected to 10 min or 60 min of myocardial ischemia by coronary ligation. The contents of succinic acid and lactic acid in myocardium corresponding to locations of MBF measurement were quantitatively analyzed by gas chromatography-mass spectrometry. In severely ischemic areas with MBF less than 20 ml/min/100g, significant increases in both succinic and lactic acids were observed 10 min after coronary occlusion. Sixty min of ischemia induced significant increase in the myocardial succinic acid content not only in severely but also in moderately ischemic areas. In contrast, lactic acid was significantly increased only in the severely ischemic area 60 min after coronary occlusion. These results indicate a good correlation between degree plus duration of myocardial ischemia and tissue succinic acid content, suggesting that its accumulation in myocardium may be a reliable and sensitive metabolic marker of coronary ligation ischemia.

Acute Disease↗
PubMedDate not supplied

Aluminum-succinate complex equilibria and their potential implications for aluminum metabolism.

Apparent contradictory results have been reported about the effect of succinate on aluminum toxicity, distribution and excretion in mice. Investigating the influence of this ligand on aluminum speciation in the main biofluids may help understand the above observations at the molecular level. In the absence of experimental access to ultrafiltrable aluminum speciation, computer simulations have been used in the gastrointestinal fluid and blood plasma, based on Al-succinate complex formation constants determined under physiological conditions. Calculations run for gastrointestinal conditions show that Al-succinate soluble complexes are formed in the 2 to 6 pH range--especially the neutral M2L(OH)4--which may enhance aluminum absorption. This influence, however, should be limited by dietary phosphate. In blood plasma, there is no possibility for succinate to mobilize a significant aluminum fraction, which confirms a recent suggestion that the possible protective effect of succinate against aluminum toxicity in mice may not be due to aluminum complexation.

Aluminum↗