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PubMed2007

Malignant paragangliomas associated with mutations in the succinate dehydrogenase D gene.

INTRODUCTION: Malignant paragangliomas have been well described in carriers of mutations of the succinate dehydrogenase B (SDHB) gene, but have rarely been associated with mutations in the succinate dehydrogenase D (SDHD) gene. AIM: The aim of the study was to report the different clinical expression patterns of malignant paragangliomas in five patients with SDHD (D92Y) mutations observed in approximately 200 SDHD (D92Y) mutation carriers followed in our institution. RESULTS: Metastasis and/or local tumor invasion was documented 0 (n=2), 1, 18, and 30 yr after the initial diagnosis of paraganglioma. Malignancy was proven by paraganglioma bone metastases (n=2), intrathoracic paraganglioma with lymph node metastases, locally invasive head-and-neck paraganglioma with destruction of the petrosal bone, and locally invasive paraganglioma of the bladder with lymph node metastases. Four of the five patients developed catecholamine excess during follow-up due to intraadrenal paraganglioma (pheochromocytoma) (n=1), extra adrenal paraganglioma (n=2), and presumed subclinical disease (n=1). CONCLUSION: SDHD mutations (D92Y) are associated with malignant paragangliomas and catecholamine excess with remarkable interindividual variations despite the same mutation. We estimate that the prevalence of malignancy in carriers of D92Y mutations is at least 2.5%.

Adrenal Gland Neoplasms↗
PubMed1999

Serum antibodies against the flavoprotein subunit of succinate dehydrogenase are sensitive markers of eye muscle autoimmunity in patients with Graves' hyperthyroidism.

Thyroid-associated ophthalmopathy is an autoimmune disorder of the extraocular muscles and orbital connective tissue, which is usually associated with Graves' hyperthyroidism. Well-studied markers of ophthalmopathy are eye muscle membrane antigens, reportedly of approximately 64-kDa molecular mass. One, originally identified only as the 64-kDa protein, has recently been shown to be the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, which has a correct molecular mass of 67 kDa. We have used purified beef heart Fp as antigen in an enzyme-linked immunosorbent assay for cross-reactive human autoantibodies. Sera have been screened from patients with thyroid-associated ophthalmopathy classified according to activity and presence or not of eye muscle disease, and from those with Graves' hyperthyroidism without eye involvement. Also examined were serum samples taken periodically from 20 patients with Graves' hyperthyroidism during 24 months of treatment of their hyperthyroidism with antithyroid drugs. Four of these patients had ophthalmopathy at the onset, 12 developed ophthalmopathy, and 4 did not develop any eye signs during treatment. Anti-Fp subunit antibodies were detected in 73% of patients with active ophthalmopathy and evidence of eye muscle involvement but only in 25% if there was only congestive ophthalmopathy. These values were 0% and 11% for patients with chronic ophthalmopathy, with or without eye muscle dysfunction, respectively. The antibodies were also detected in 14% of patients with Graves' hyperthyroidism without evident ophthalmopathy, 11% of patients with nonimmunologic thyroid disorders, 12% of type I diabetics, and 12% of age- and sex-matched normal subjects. Significantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves' hyperthyroidism, who developed eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient. Antibodies were not detected in any of 6 patients who developed congestive ophthalmopathy without evidence of eye muscle damage or in 4 patients who did not develop any eye signs. In conclusion, we have shown a close relationship between eye muscle disease and serum antibodies against the Fp subunit of succinate dehydrogenase in patients with Graves' hyperthyroidism.

Adult↗
PubMed2003

Clinical spectrum of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting CNS gamma-aminobutyric acid (GABA) degradation. SSADH, in conjunction with GABA transaminase, converts GABA to succinate. In the absence of SSADH, GABA is converted to 4-OH-butyrate. The presence of 4-OH-butyrate, a highly volatile compound, may be undetected on routine organic acid analysis. Urine organic acid testing was modified at the authors' institution in 1999 to screen for the excretion of 4-OH-butyrate by selective ion monitoring gas chromatography-mass spectrometry in addition to total ion chromatography. Since then, five patients with 4-hydroxybutyric aciduria have been identified. The authors add the clinical, neuroimaging, and EEG findings from a new cohort of patients to 51 patients reported in the literature with clinical details. Ages ranged from 1 to 21 years at diagnosis. Clinical findings include mild-moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI performed in five patients at the authors' institution revealed symmetric increased T2 signal in the globus pallidi. SSADH deficiency is an under-recognized, potentially manageable neurometabolic disorder. Urine organic acid analysis should include a sensitive method for the detection of 4-hydroxybutyrate and should be obtained from patients with mental retardation or neuropsychiatric disturbance of unknown etiology.

Adolescent↗
PubMed2001

Characterization of bioconversion of fumarate to succinate by alginate immobilized Enterococcus faecalis RKY1.

In this study, the immobilization characteristics of Enterococcus faecalis RKY1 for succinate production were examined. At first, three natural polymers--agar, kappa-carrageenan, and sodium alginate--were tried as immobilizing matrices. Among these, sodium alginate was selected as the best gel for immobilization of E. faecalis RKY1. Efficient conditions for immobilization were established to be with a 2% (w/v) sodium alginate solution and 2-mm-diameter bead. The bioconversion characteristics of the immobilized cells at various pH values and temperatures were examined and compared with those of free cells. The optimum pH and temperature of the immobilized cells were the same as for free cells, 7.0 and 38 degrees C respectively, but the conversion ratio was higher by immobilization for all the other pH and temperature conditions tested. When the seed volume of the immobilized cells was adjusted to 10% (v/v), 30 g/L of fumarate was completely converted to succinate (0.973 g/g conversion ratio) after 12 h. In addition, the immobilized cells maintained a conversion ratio of >0.95 g/g during 4 wk of storage at 4 degrees C in a 2% (w/v) CaCl2 solution. In repetitive bioconversion experiments, the activity of the immobilized cells decreased linearly according to the number of times of reuse.

Alginates↗
PubMed1988

Comparison of the subrenal capsule assay and succinate dehydrogenase inhibition test as drug sensitivity tests for cancer.

The same chemotherapeutic agents were tested against fresh surgical explants of solid tumors obtained from 50 patients using the in vivo subrenal capsule (SRC) assay and the in vitro succinate dehydrogenase inhibition (SDI) test in comparison. Control growth adequate to meet evaluable assay criteria was obtained in 36 of the 50 tumors tested in the SRC assay (72.0%). In the SDI test, 46 of 50 tumors were evaluable (92.0%). Correlations between the two test systems were dependent upon the activity criteria established for each system. With activity criteria set at a change of less than or equal to -2.0 in the drug sensitivity score for the SRC assay and greater than or equal to 50.0% inhibition of succinate dehydrogenase activity for the SDI test, 12.5% of the drugs tested were active in the SRC assay and 22.3% were active in the SDI test. Correlations of tumor response between the two test systems were 31.7% for sensitivity (13/41) and 95.1% for resistance (98/103). In spite of the fundamental difference between the SRC assay and SDI test, meaningful correlations between the test results and clinical tumor responses in both test systems were obtained. This fact suggests that the two methods are complementary to each other.

Animals↗
PubMed2004

Successful treatment with succinate in a patient with MELAS.

We present a case report of a 27-year-old man with MELAS, who presented with general convulsions and left flaccid hemiparesis. Anticonvulsant drugs failed to achieve complete control of his convulsions. A good response to oral administration of succinate has been maintained for more than 30 months, with no recurrence of any stroke-like episode. Succinate therapy may have potential for treatment of uncontrolled convulsive MELAS patients.

Administration, Oral↗
PubMed1987

Short-chain fatty acids and succinate in feces of healthy human volunteers and their correlation with anaerobe cultural counts.

Short-chain fatty acids (SCFA) and succinate in fresh feces from 10 healthy human volunteers were detected with gas-liquid chromatography and were correlated with their fecal cultural counts. The SCFA content of feces did not change significantly after freezing, but the cultural counts of total anaerobes and bifidobacteria showed significant changes (0.001 less than P less than 0.01). A significant negative correlation (r = -0.78; 0.01 less than P less than 0.02) was found between the bifidobacteria cultural counts and the succinic acid concentration in fresh feces, which disappeared after freezing of the samples. Because of the significant differences in cultural counts and the shift in significant correlations after freezing, it is important to use fresh fecal samples for these correlation studies. Lactic acid and i-caproic acid were not found in the fecal samples. The results show that SCFA and organic acid concentrations cannot replace (an)aerobe cultural counts in fecal flora studies of healthy human volunteers because of the low rate of significant correlations between these two.

Adult↗
PubMed1984

Kinetics of succinic dehydrogenase inhibition by methyl parathion and its recovery by oximes and L-cysteine in hepatopancreas of Lamellidens marginalis.

Effects in vitro of methyl parathion on some kinetic constants of succinic dehydrogenase (SDH) in hepatopancreas of freshwater mussel, L. marginalis were studied. Altered pH vs. specific activity curves for SDH demonstrated significant inhibition by methyl parathion in buffered acidic, neutral and alkaline ranges. At high pH ranges IC50 (12.5 microM) of methyl parathion did not cause 50% inhibition enzyme as it did at neutral and acidic pHs. Activation energies (delta E) were found to be increased suggesting decreased efficiency of enzyme in presence of methyl parathion. Non-competitive inhibition with respect to activation by succinate was indicated by decreased maximal velocity (V) without change in Michaelis Menten constant (Km). Pyridine-2-aldoxime (25 microM), pyridine-4-aldoxime (15 microM) and L-cysteine (40 microM) neutralized the inhibition of SDH by methyl parathion (12.5 microM). The kinetic data suggests that inhibition of SDH by methyl parathion was pH and temperature independent.

Animals↗
PubMed1989

Succinate dehydrogenase and synthetic pathways of glucose 6-phosphate are also the markers of the toxicity of orally administered secondary autoxidation products of linoleic acid in rat liver.

In order to find the markers of the toxicity of the autoxidized lipids in the liver, rats were given a lethal amount of secondary autoxidation products of linoleic acid (400 mg/rat/day for 3 days) and then changes in the hepatic metabolic functions were analyzed. A decrease in acetyl-CoA level to half caused by the depletion of CoASH was reported in an associated paper (J. Nutr. Sci. Vitaminol., 35, 11-23, 1989). Citrate, isocitrate, and 2-oxoglutarate also decreased to half the level of those of the control group. Reduction in isocitrate dehydrogenase activity was only 25%, while NADH2 and ATP levels remained unchanged. Thus, the reduction in the citrate cycle activity was due to the decrease in acetyl-CoA. The activity of mitochondrial succinate dehydrogenase was decreased to 1/5. Other appreciable changes were depletion of glucose 6-phosphate and fructose 6-phosphate, accumulation of glucose 1-phosphate, reductions in hexokinase, phosphofructokinase, glucose-6-phosphatase, phosphoglucomutase, and phosphogluconate dehydrogenase activities, and decrease in the NADPH2 level. It was considered that these changes were caused by the depletion of glucose 6-phosphate whose synthetic pathways were abnormal. Therefore, the markers of the hepatotoxicity of secondary products were the changes in the CoASH level and the activities of succinate dehydrogenase and synthetic pathways for glucose 6-phosphate.

Animals↗
PubMed1991

Dehydroandrographolide succinic acid monoester as an inhibitor against the human immunodeficiency virus.

Dehydroandrographolide succinic acid monoester (DASM) is the dehydroandrographolyl ester of succinic acid; and andrographolide, from which DASM is made, is the major diterpenoid lactone found in the Chinese medicinal herb, Andrographis paniculata. DASM has been found to be an inhibitor against the human immunodeficiency virus (HIV) in vitro. It was nontoxic to the H9 cell at the concentrations of 50-200 (average, 108) micrograms/ml and was inhibitory to the HIV-1 (IIIB) at the minimal concentration of 1.6-3.1 (average 2.0) micrograms/ml. It was also inhibitory to two other strains of HIV-1 and a strain of HIV-2. This inhibitory effect could also be demonstrated in cultures of activated human blood mononuclear cells; the 50% toxic dose and the 50% HIV inhibitory dose were about 200-greater than or equal to 400 and 0.8-2 micrograms/ml, respectively. At the subtoxic concentration, DASM partially interfered with HIV-induced cell fusion and with the binding of HIV to the H9 cell. Presumably, it also interfered with HIV replication at another unidentified step(s).

Antiviral Agents↗
PubMed2000

Stimulation of insulin release in hereditarily diabetic rats by mixed molecules formed of nateglinide and a succinic acid ester.

Hereditarily diabetic Goto-Kakizaki rats were infused for 5 min with saline, containing as required nateglinide or mixed molecules (HD154 and HD166) with both a nateglinide moiety and a succinic acid ester moiety. The dose of these agents given intravenously amounted to 5.0 nmol/g body weight in all cases. All agents provoked a comparable early increase in plasma insulin concentration. However, HD154 and HD166, but not nateglinide itself, also caused a secondary rise in plasma insulin concentration 30 min after their infusion. It is proposed that mixed molecules formed of both a hypoglycemic sulfonylurea or meglitinide analog and a succinic acid ester may be better able than the antidiabetic agents themselves to evoke a sustained stimulation of insulin release in non-insulin-dependent diabetes.

Animals↗
PubMed2000

Prolongation of the insulinotropic action of glucagon-like peptide 1 by the dimethyl ester of succinic acid in an animal model of type-2 diabetes.

Adult rats, that had been injected with streptozotocin during the neonatal period, received a primed constant infusion of succinic acid dimethyl ester (SAD; 0.5 micromol followed by 0.25 micromol x min(-1), both per g body wt.) in saline for 15 min and, at the 5th min of such an infusion, an intravenous injection of GLP-1 (5 pmol per g body wt.). Within 2 min, the ester increased the plasma insulin concentration by 0.33+/-0.05 nM. Likewise, within 2 min, GLP-1 provoked a marked increase in plasma insulin concentration; such an increase was comparable in rats infused with either saline or SAD, with an overall mean value of 0.93+/-0.07 nM. In the rats infused with SAD, however, the secretory response to GLP-1 appeared more sustained than in the saline-infused animals. For instance, the paired ratio for the insulinogenic index at 10/2 min after GLP-1 injection averaged 30.5+/-4.0% in SAD-infused rats, as compared (P<0.025) to only 17.0+/-2.5% in saline-infused animals. These findings suggest that succinic acid esters could be used to prolong the insulinotropic action of GLP-1 in the treatment of type-2 diabetes.

Animals↗
PubMed1998

The influence of glucose, succinate, pH of the medium and higher temperature on the cytotoxic activity of the preparation Ukrain.

Cells of ascitic forms of Ehrlich's carcinoma and sarcoma 37 transplanted into C57BI/6 mice were used to study the influence of glucose, succinate, and pH of the medium on the cytotoxic activity of the preparation Ukrain. Viability of cells was estimated by the method of intravital staining with tripan blue after the incubation of cell suspension in the presence of the preparation (1.05 x 10(-5) mol and 1.69 x 10(-4) mol). It was established that glucose (5 mmol) reduces the cytotoxic activity of Ukrain, while succinate (5 mmol) increases it. The activity of the preparation was practically absent at pH 6.1-6.7 of the incubation medium and was at a maximum at pH 7.3-8.0. A temperature of 41.5 degrees C has no influence on the effectiveness of Ukrain.

Alkaloids↗
PubMed1976

[Effect of sodium succinate on several carbohydrate metabolism indices of ischemic myocardium].

The influence of sodium succinate on the content of lactic, pyruvic acids and glucose in the venous blood flowing from the ischemic zone of the myocardium was studied in dogs with ligated coronary artery. The intracoronary injection of the preparation in doses of 2 and 10 mg/kg diminished the content of blood lactic acid flowing from the ischemic zone; a dose of 10 mg/kg decreased the consumption of glucose by the ischemic myocardium. Sodium succinate (100 mg/kg) intravenously reduced the content of the lactic acid significantly and inhibited the glucose consumption by the ischemic myocardium, with its increase in the arterial blood. A fall of lactacidemia can be connected with the activation of Krebs cycle and an increase of oxygen utilization by the ischemic myocardium.

Animals↗
PubMedDate not supplied

[Effect of surgical thread from the dura mater, modified with succinate, on the energy metabolism of white rat kidney mitochondria].

The activity of energy metabolism has been studied in the experiment with white rats, which had been carried out nephrotomia with following use for suture such absorbable surgical threads as catgut plain, biofil (of dura mater spinalis of the cattle) and biofil modified with succinate. The research proves the use of catgut plain decreases of energy quotient and such polarographic index as the rate of phosphorylating respiration of mitochondria of the kidneys in postoperative period. The greater activity of energy metabolism during this period has been stated with the use of biofil. The use of biofil modified with succinate results in the activation of bioenergy processes.

Animals↗
PubMed1999

[The effect of sodium alpha-glutarate on enzymatic transamination activity and on succinate dehydrogenase in rats with different resistances to hypoxia].

It have been found that intraperitoneal alpha-ketoglutarate injection (20 mg/100 g body weight) results in increase in the influence of cholinergic regulation mechanisms. It also results in increase of aminotransferase activity on background of the decrease of succinate dehydrogenase activity in liver and pancreas tissues and in small intestines mucous. Activity of transamination enzymes and succinate dehydrogenase activity is much higher in the case of rats with high hypoxia resistance, alpha-ketoglutarate injection results in increase of transamination enzymes activity in the organisms of rats with low resistance to hypoxia up to the control level of rats with high resistance, and simultaneously increases rats resistance to hypoxia. Effect of alpha-ketoglutarate injection on the energetical exchange in the tissues with different parasympathetic dependence taking from the animals with different hypoxia resistance is suppressed by blockade of M- and H-cholinoceptors.

Amination↗
PubMed2000

Inhibition of mitochondrial succinate oxidation by antipsychotic medication.

Fourteen antipsychotics of 5 different chemical classes were tested for their effects on mitochondrial succinate oxidation. Each of the compounds tested, with the exception of haloperidol, phenothiazine and prochlorperazine, inhibited succinate oxidation. The apparent inhibition constant for phenothiazine derivatives declined with increasing values of the partition coefficient.

Animals↗
PubMed1975

Escherichia coli succinic thiolinase. Stoichiometry of phosphorylation and coenzyme A binding.

Equilibrium and covalent binding studies of succinic thiokinase from Escherichia coli indicates that there can be a stoichiometric relationship between coenzyme A binding and the phosphoyrlation capacity of the enzyme. A comparison of homogeneous enzyme preparations has revealed that enzyme of high specific activity exhibits greater binding capacity and that this property is proportional to enzyme activity. Phosphorylation capacity was related to specific activity in highly active enzyme preparations, but leveled off at 1 mol of phosphorus/mol of thiokinase. These studies show that the "dimer of dimers" structure of succinic thiokinase contains the expected two active sites and that this enzyme does not demonstrate "half-the-sites" reactivity. A coenzyme A binding site of lower affinity can be detected in some enzyme samples of lower specific activity. Binding of coenzyme A to the higher affinity sites may involve positive cooperativity. ATP, unlike ADP, does not bind to phosphorylated enzyme.

Adenosine Diphosphate↗