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PubMed1991

Plasma alpha-tocopherol profiles in sheep after oral administration of dl-alpha-tocopheryl acetate and d-alpha-tocopheryl succinate.

The purpose of this study was to compare the bioavailability of dl-alpha-tocopheryl acetate and d-alpha-tocopheryl succinate when administered to sheep in a single oral dose weekly. The sheep, five per treatment, were given a basal diet without vitamin E supplement (control) or basal diet with weekly administration of 2225 IU of dl-alpha-tocopheryl acetate, 2225 IU of d-alpha-tocopheryl succinate, or 6675 IU of d-alpha-tocopheryl succinate. Increases in plasma alpha-tocopherol concentration levels over the 3-wk period of study were determined and compared. The greater availability of dl-alpha-tocopheryl acetate was indicated by the significantly higher peak plasma alpha-tocopherol concentrations and the greater area under the curve produced by administration of the acetate than the succinate esters at the same dosage. Reported data on plasma alpha-tocopherol concentrations suggest that bioavailability in sheep of d-alpha-tocopheryl succinate versus dl-alpha-tocopheryl acetate is 3:1.

Administration, Oral↗
PubMed1983

Study on the specificity of alpha-tocopheryl (vitamin E) acid succinate effects on melanoma, glioma and neuroblastoma cells in culture.

d- and dl-alpha-tocopheryl succinate inhibited growth and caused morphological changes in mouse melanoma (B-16), mouse neuroblastoma (NBP2), and rat glioma (C-6) cells in culture. To study whether the effects of alpha-tocopheryl (vitamin E) succinate on tumor cells are mediated by antioxidant mechanisms, the effects of lipid-soluble antioxidants, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) were compared with those of vitamin E succinate. Results showed that these antioxidants produced alterations on the growth and morphology of neuroblastoma, melanoma, and glioma cells which are similar to those produced by vitamin E succinate; however, the extent of the effect depended upon the type of antioxidant and the form of tumor cells. These data suggest that the effects of vitamin E succinate on tumor cells may be mediated, in part, by antioxidant mechanisms.

Animals↗
PubMed1991

Anaphylactoid reaction to intravenous hydrocortisone sodium succinate: a case report and literature review.

Reports of corticosteroid sensitivity reactions are rare in the medical literature. We report an anaphylactoid reaction to hydrocortisone sodium succinate given intravenously which occurred on two occasions during treatment of a patient for asthma. Intradermal testing with a wide range of steroid preparations gave positive results with hydrocortisone sodium succinate, methylprednisolone sodium succinate, methylprednisolone sodium succinate and methylprednisolone acetate. No reactions occurred to dexamethasone sodium phosphate administered intravenously, prednisolone given orally or beclomethasone dipropionate by inhalation. Results of a radioallergosorbent test (RAST) were negative for hydrocortisone sodium succinate.

Administration, Inhalation↗
PubMed2005

Nasal drug delivery of sumatriptan succinate.

The purpose of this work was to increase the nasal absorption of sumatriptan succinate by using bile salts. A rat in situ nasal perfusion technique was used to examine the rate and extent of absorption of sumatriptan succinate. In vitro enzymatic drug degradation studies were carried out with rat nasal washings. Various experimental conditions such as nasal perfusion rate, pH of the perfusion medium and concentrations of absorption enhancers such as sodium deoxycholate, sodium caprate, sodium tauroglycocholate and EDTA were optimized. In vivo studies were carried out for the optimized formulation in rabbits and the pharmacokinetics parameters of nasal solution were compared with marketed nasal solutions. Nasal absorption of sumatriptan succinate was pH dependent. It was found maximum at pH 5.5 and decreased at higher pH values. In in vitro enzymatic degradation studies, no measurable degradation was observed during the first week. The extent of drug absorption was increased by absorption enhancers. Sodium deoxycholate appeared to be more effective for enhancing the nasal absorption of sumatriptan succinate than the other absorption enhancers. The order of increasing absorption of sumatriptan succinate caused by theenhancers was sodium deoxycholate > sodium caprate > sodium tauroglycocholate > EDTA.

Absorption↗
PubMed1998

Bioconversion of fumaric acid to succinic acid by recombinant E. coli.

Succinic acid was produced efficiently from fumaric acid by a recombinant E. coli strain DH5 alpha/pGC1002 containing multicopy fumarate reductase genes. The effects of initial fumaric acid and glucose concentration on the production of succinic acid were investigated. Succinic acid reached 41 to over 60 g/L in 48.5 h starting with 50 to 64 g/L fumaric acid. Significant substrate inhibition was observed at initial fumaric acid concentration of 90 g/L. L-Malic acid became the major fermentation product under these conditions. Provision of glucose (5-30 g/L) to the fermentation medium stimulated the initial succinic acid production rate over two folds.

Acetic Acid↗
PubMed1989

Cerebral resuscitation with succinate and fructose-1, 6-diphosphate.

To test the hypotheses that succinate or fructose-1, 6-diphosphate may have a beneficial effect in global cerebral ischemia, we induced complete global cerebral ischemia for 5 minutes in rabbits by occlusion of the ascending aorta and the superior and inferior vena cavae. Fifteen minutes after restoration of cerebral blood flow, animals received an intravenous bolus of either succinate or fructose-1,6-diphosphate followed by continuous infusion. Another group of animals received fructose-1, 6-diphosphate beginning prior to aortic occlusion. Control animals received intravenous glucose by bolus, followed by infusion. Cerebrospinal fluid lactate levels were measured before occlusion and at 2 1/2 hours after occlusion, when the animals were sacrificed. In all animals electrocortical silence was demonstrated for the 5 minutes of global ischemia. The percent change in cerebrospinal fluid lactate levels in all groups was statistically similar. Only two of seven of the control animals recovered electroencephalogram amplitude during the 2 1/2 hour observation period. Time for recovery of amplitude on the electroencephalogram in animals receiving fructose-1, 6-diphosphate either before or after ischemia was statistically similar to controls. In the succinate treated group, all seven animals regained preocclusion levels of electroencephalogram amplitude within 36 minutes of the restoration of cerebral blood flow. Succinate administered after complete global cerebral ischemia resulted in significantly increased recovery of cerebral electrical activity (Fischer's exact test, p less than 0.05).

Animals↗
PubMed1993

Sources of acetyl-CoA entering the tricarboxylic acid cycle as determined by analysis of succinate 13C isotopomers.

A new 13C NMR technique for measuring substrate utilization by the citric acid cycle based on an analysis of succinate 13C isotopomers is presented. The relative contribution of up to three different labeling patterns in acetyl-CoA entering the citric acid cycle may be determined under non-steady-state conditions. We present experimental data from perfused rat hearts subjected to a brief period of ischemia, where both succinate and glutamate resonances were observed in the 13C spectrum. The contributions of labeled exogenous acetate and lactate and unlabeled sources to the acetyl-CoA pool were compared using this succinate analysis and a previously published glutamate analysis [Malloy et al. (1990) Biochemistry 29, 6756-6761], and the two methods give identical results. This indicates that the succinate and glutamate isotopomers originated from a common alpha-ketoglutarate pool, verifying that glutamate is in isotopomeric equilibrium with alpha-ketoglutarate under these conditions.

Acetyl Coenzyme A↗
PubMed1984

Energetics of ATP-driven reverse electron transfer from cytochrome c to fumarate and from succinate to NAD in submitochondrial particles.

The maximum Gibbs free energies of reverse electron transfer from succinate to NAD+ and from cytochrome c to fumarate driven by ATP hydrolysis in submitochondrial particles from beef heart were measured as a function of the Gibbs free energy of ATP hydrolysis. The ratio of the energies delta G'redox/delta G'ATP was 1.40 from succinate to NAD+ and 0.89 from cytochrome c to succinate. The ratio, equivalent to a thermodynamic P/2e-ratio, was dependent on whether the electrochemical proton gradient was primarily a membrane potential or a pH gradient for the cytochrome c to fumarate reaction. The results are consistent with H+/ATP = 3 for F1 ATPase, H+/2e- = 4 for NADH-CoQ reductase, and H+(matrix)/2e- = 2 for succinate-cytochrome c reductase.

Adenosine Triphosphate↗
PubMed1987

The inhibitory effect of succinate on radiation-enhanced mitochondrial lipid peroxidation.

The degree of mitochondrial ADP/Fe/NADPH-induced lipid peroxidation was increased up to the fourth day after 9.0 Gy whole body gamma-irradiation. The lipid peroxidation inhibiting effect of succinate added to isolated mitochondria was diminished as a consequence of irradiation. The succinate, administered in vivo prior to irradiation, decreased the amount of malondialdehyde production and protected the succinate dehydrogenase enzyme against inactivation. The mean survival of succinate-pretreated animals was much longer than that of controls. The role of mitochondrial lipid peroxidation in the pathogenesis of radiation injury is discussed.

Adenosine Diphosphate↗
PubMed1960

Succinic dehydrogenase and cytochrome oxidase activities in cell cultures.

Succinic dehydrogenase and cytochrome oxidase have been assayed in permanent cell lines (HEP 1, HEP 2, and HLM), in short-term cultures of chick embryo heart cells, and in various tissues. Their activities in different cells are compared by relating them to deoxyribonucleic acid. They are very low in HEP 1, HEP 2, and HLM cells by comparison with the activities in any normal tissues examined. All the succinic dehydrogenase was shown to be located in the mitochondria of the permanent cell lines by staining with tetrazolium derivatives. Both enzymes were more active in tissues of 19-day chick embryos than in those of 11- or 14-day embryos. The increasing activities found during normal development were quickly curtailed or reversed when heart cells were grown as monolayer cultures. Digitonin-treated mitochondria produced preparations with much higher activities of cytochrome oxidase than untreated samples. Activities measured in this way were again very much lower in HEP 1, HEP 2, and HLM cells than in the normal tissues. From the derived ratio of cytochrome oxidase:succinic dehydrogenase, it was apparent that cytochrome oxidase is diminished to a greater extent than succinic dehydrogenase in both permanent cell lines and short-term cultures, by comparison with the corresponding activities in embryonic and adult tissues. The features common to the metabolism of proliferating cells in vitro and malignant cells are discussed.

Animals↗
PubMed1993

Severity of promotion by sodium salts of succinic acid in rat urinary bladder carcinogenesis correlates with sodium ion concentration under conditions of equal urinary pH.

Elevation of urinary pH and Na ion concentration induced by feeding high doses of sodium salts plays a crucial role in promotion of urinary bladder carcinogenesis in male rats initially treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). In the present study, urinary bladder carcinogenesis in male F344 rats was promoted by feeding the mono- and di-sodium salts of succinic acid, and the activity was enhanced by varying urinary sodium ion concentration under conditions of equally high pH. In Experiment 1, the rats were given 0.05% BBN in their drinking water for 4 weeks and then fed basal diet containing 5% succinic acid, 5% sodium succinate (Na-Suc) or 5% di-sodium succinate (2Na-Suc) for 32 weeks. The development of carcinomas in the urinary bladder was enhanced by treatment with Na-Suc and with 2Na-Suc. 2Na-Suc induced larger urinary bladder tumors than the Na-Suc. In Experiment 2, 5% Na-Suc and/or 5% 2Na-Suc were fed to the rats for 8 weeks without prior BBN treatment. Induction of simple hyperplasia as observed by light microscopy, was greater in rats fed 2Na-Suc than Na-Suc. Increased 5-bromo-2'-deoxyuridine labeling index and alterations of the urothelial surface observed by scanning electron microscopy of the urinary bladder were similarly greater in rats fed 2Na-Suc compared to Na-Suc. In addition, there was a tendency toward increased spermidine/spermine N1-acetyltransferase activity in the urinary bladder epithelium of rats fed 5% 2Na-Suc. The results of Experiment 2 corresponded to differences in promoting activity for the different chemicals in Experiment 1. Thus, tumor growth was associated with sodium ion concentration level under conditions of equal increase of urinary pH.

Animals↗
PubMed2005

Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions.

The genes encoding succinate dehydrogenase (SDH) subunits B, C and D, act as tumour suppressors in neuro-endocrine tissues. Tumour formation has been associated with succinate accumulation. In paraganglioma cells, two forms of SDHA (type I, II) were found which might preclude significant succinate accumulation in the case of a mutation in either form. In fibroblasts only SDHA type I is found. In these cells, SDHA type I mutation leads to SDH deficiency, succinate accumulation and hypoxia-inducible factor 1alpha(HIF1alpha) nuclear translocation. HIF1alpha nuclear translocation was not observed in ATPase-deficient fibroblasts with increased superoxide production and was found to be independent of cellular iron availability in SDHA-mutant cells. This suggests that neither superoxides nor iron were causative of HIF1alpha nuclear translocation. Conversely, alpha-ketoglutarate (alpha-KG) inhibits this nuclear translocation. Therefore, the pseudo-hypoxia pathway in SDH-deficient cells depends on the HIF1alphaprolyl hydroxylase product/substrate (succinate/alpha-KG) equilibrium. In SDH deficiency, organic acids thus appear instrumental in the HIF1alpha-dependent cascade suggesting a direct link between SDH and tumourigenesis.

Blotting, Western↗
PubMed1992

Energy conservation by succinate decarboxylation in Veillonella parvula.

Veillonella parvula cannot grow with succinate as sole energy source. However, succinate decarboxylation simultaneous with malate or lactate fermentation increased growth yields by 2.4-3.5 g (mol succinate)-1. Malate was fermented stoichiometrically to acetate and propionate whereas lactate fermentation produced more acetate and considerable amounts of H2. Aspartate was utilized only in the presence of succinate as co-substrate. Methylmalonyl-CoA decarboxylase and ATP-dependent pyruvate carboxylase, but not methylmalonyl-CoA:pyruvate transcarboxylase, were detected in cell-free extracts of malate- or lactate-grown cells. The energetic aspects of these fermentation patterns are discussed.

Acetates↗
PubMed1976

Reactivity of the sulfhydryl groups of soluble succinate dehydrogenase.

Soluble succinate dehydrogenase prepared by butanol extraction reacts with N-ethylmaleimide according to first-order kinetics with respect to both remaining active enzyme and the inhibitor concentration. Binding of the sulfhydryl groups of the enzyme prevents its alkylation by N-ethylmaleimide and inhibition by oxaloacetate. A kinetic analysis of the inactivation of alkylating reagent in the presence of succinate or malonate suggests that N-ethylmaleimide acts as a site-directed inhibitor. The apparent first-order rate constant of alkylation increases between pH 5.8 and 7.8 indicating a pKa value for the enzyme sulfhydryl group equal to 7.0 at 22 degrees C in 50 mM Tris-sufate buffer. Certain anions (phosphate, citrate, maleate and acetate) decrease the reactivity of the enzyme towards the alkylating reagent. Succinate/phenazine methosulfate reductase activity measured in the presence of a saturating concentration of succinate shows the same pH-dependence as the alkylation rate by N-ethylmaleimide. The mechanism of the first step of succinate oxidation, including a nucleophilic attack of substrate by the active-site sulfhydryl group, is discussed.

Binding Sites↗
PubMed1959

The effect of piperazine on succinate production by Ascaris lumbricoides.

Piperazine reduced the production of succinate by Ascaris lumbricoides. This effect was reversible. There was a close parallelism between the concentrations of piperazine which paralysed the worm and those which inhibited the formation of succinate. Piperazine did not affect the incorporation of [2-(14)C]lactate into succinate by strips of Ascaris muscle. It was concluded that production of succinate supplies energy for the contraction of Ascaris muscle.

Animals↗
PubMed1985

Electrophysiology of succinate transport across rabbit renal brush border membranes.

In rabbit renal brush border membrane vesicles, the membrane potential was monitored using a voltage-sensitive optical probe (diS-C3-(5)). The ionic dependence of the electrogenic Na+/succinate co-transporter was determined in the presence of monovalent anions and mono-, di-, and trivalent cations. Na+ and La3+ were the only cations capable of supporting a succinate-dependent membrane depolarization: Li+, K+, Rb+, Cs+, NH4+, Hg2+, Ca2+, Ba2+, Sr2+, Mg2+, Cu2+, Fe2+, Cd2+, Be2+, Pb2+, Zn2+, Mn2+ and Co2+ did not. Succinate increased the Na+ permeability of the brush border membrane in a saturable manner: saturating succinate (3 mM) concentrations increased the Na+/K+ permeability (PNa/PK) ratio from 0.6 to 2.3. In the presence of Na+, Li+ and Hg2+ inhibit the succinate potential: cis-Li+ inhibition is competitive with an apparent Ki of 2 mM, while trans-Li+ is noncompetitive; cis-Hg2+ decreased the maximal depolarization with an inhibitor constant Ki of 8 microM, and this effect was irreversible. Cations having no effect included K+, Rb+, Cs+, NH4+, Ba2+, Ca2+, Mg2+, Sr2+, Cu2+, Fe2+, Cd2+, Co2+, Be2+, Zn2+, Pb2+, Mn2+, and La3+. It is concluded that succinate/Na+ co-transport produces a specific increase in the Na+ conductance of renal brush borders.

Animals↗
PubMed1987

The Bacteroides by-product succinic acid inhibits neutrophil respiratory burst by reducing intracellular pH.

Short-chain fatty acids, particularly succinic acid, are major metabolic by-products of Bacteroides species. To determine their role as potential virulence factors in infections containing Bacteroides species, short-chain fatty acids were examined for their effect on the neutrophil respiratory burst. Succinate (30 to 50 mM) irreversibly impaired superoxide and hydrogen peroxide production in response to opsonized zymosan and phorbol myristate acetate when neutrophils were treated at pH 5.5 but not pH 6.0 or greater. Several other short-chain fatty acids tested produced similar inhibition. Reversible inhibition of oxygen consumption was found when neutrophils were incubated in succinate-containing medium (pH 6.0) as well as control medium (pH 6.0 and 5.5). Neutrophil cytoplasmic pH was measured by fluorimetric techniques to determine whether the inhibition was mediated via a reduction in intracellular pH. The intracellular pH of cells in control medium (pH 6.5 or less) was significantly reduced compared with pH 7.4. The addition of succinate (30 mM) to these media caused a further significant reduction in cytoplasmic pH at each pH level. The reduction in intracellular pH was sufficient to account for both the irreversible and reversible impairment of the neutrophil respiratory burst. Thus, short-chain fatty acids appear to exert their inhibition, at least in part, by reducing intracellular pH. These data also demonstrate the potential for interactions between Bacteroides species and their microenvironment to increase the virulence of an infection.

Bacteroides↗
PubMed1973

Genetic and biochemical characterization of mutants of Bacillus subtilis defective in succinate dehydrogenase.

Eleven succinate-accumulating mutants of Bacillus subtilis have been mapped by transformation and transduction crosses and characterized with respect to activities of citric acid cycle enzymes. These mutants could be divided into three genetic groups. Nine of the mutants were found to map between argA and leu in the citF locus. A second group was located between lys-1 and trpC2 and the third group could not be located on the B. subtilis chromosome in extensive transduction crosses. All of the citF mutants lack detectable succinate dehydrogenase activity, whereas both of the other groups show a reduced level of this enzyme. In addition, most of the mutants in the citF locus lack cytochrome a, whereas the level of this cytochrome is normal in the other two groups. A procedure has been devised for the solubilization of the succinate dehydrogenase from the membrane of B. subtilis with the non-ionic detergent Brij 58. Some properties of the soluble and bound forms of succinate dehydrogenase are described.

Bacillus subtilis↗