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PubMed1986

[The NMR study of succinate formation from exogenous precursors in anaerobic rat heart mitochondria].

Succinate formation during incubation of isolated rat heart mitochondria with exogenous precursors, malate, alpha-ketoglutarate, oxaloacetate and L-glutamate was studied in the absence of aeration. The formation of succinate, the end product of the tricarboxylic acid cycle, occurs via two pathways: through reduction of oxaloacetate or malate and via oxiation of alpha-ketoglutarate. The highest rate of succinate synthesis was observed when mitochondria were incubated with a mixture of 5 mM L-glutamate and 10 mM oxaloacetate, i.e., when both routes were used simultaneously. The [U-13C]succinate/succinate and aspartate/succinate ratios were equal to 2, when mitochondria were incubated with 5 mM [U-13C]glutamate and 10 mM oxaloacetate. Therefore, the amount of succinate formed from [13C]alpha-ketoglutarate via transamination of [13C]glutamate with oxaloacetate exceeds twice succinate production from oxialoacetate. These data suggest that GTP formation in the succinic thiokinase reaction should exceed twice the ATP yield coupled with NADH-dependent reduction of fumarate.

Anaerobiosis↗
PubMed1984

[Interaction of succinate dehydrogenase and oxaloacetate].

The equilibrium and rate constants for interaction of the reduced and oxidized membrane-bound succinate dehydrogenase (EC 1.3.99.1) with oxaloacetate were determined. The 10-fold decrease in the oxaloacetate affinity for the reduced enzyme was shown to be due to the 10-fold increase of the enzyme-inhibitor complex dissociation rate, which occurs upon its reduction. The rate of dissociation induced by succinate is 10 times higher than that induced by malonate in the submitochondrial particles, being equal in the soluble enzyme preparations. The rates of dissociation induced by malonate excess, or by the enzyme irreversibly utilizing oxaloacetate (transaminase in the presence of glutamate) are also equal. The data obtained suggest that succinate dehydrogenase interaction with succinate and oxaloacetate results from the competition for a single dicarboxylate-specific site. In submitochondrial particles all succinate dehydrogenase molecules are in redox equilibrium provided for by endogenous ubiquinone. No electronic equilibrium between the individual enzyme molecules exists, when succinate dehydrogenase is solubilized.

Enzyme Activation↗
PubMed1987

Isolation of succinate dehydrogenase from Desulfobulbus elongatus, a propionate oxidizing, sulfate reducing bacterium.

Succinate dehydrogenase was purified from the particulate fraction of Desulfobulbus. The enzyme catalyzed both fumarate reduction and succinate oxidation but the rate of fumarate reduction was 8-times less than that of succinate oxidation. Quantitative analysis showed the presence of 1 mol of covalently bound flavin and 1 mol of cytochrome b per mol of succinate dehydrogenase. The enzyme contained three subunits with molecular mass 68.5, 27.5 and 22 kDa. EPR spectroscopy indicated the presence of at least two iron sulfur clusters. 2-Heptyl-4-hydroxy-quinoline-N-oxide inhibited the electron-transfer between succinate dehydrogenase and a high redox potential cytochrome c3 from Desulfobulbus elongatus.

Bacteria↗
PubMed1988

Combined effect of adenosine 3',5'-cyclic monophosphate stimulating agents, vitamin E succinate, and heat on the survival of murine B-16 melanoma cells in culture.

An elevation of the intracellular level of cAMP by 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (R020-1724) during heat treatment (41 degrees C for 10 hours) markedly reduced the survival of murine B-16 melanoma cells in culture; however, heat alone or R020-1724 treatment at 37 degrees C for 10 hours was ineffective. D-alpha-tocopheryl succinate (vitamin E succinate), which did not increase cAMP level, reduced the survival of heated cells to a greater degree than with vitamin E succinate alone. The presence of vitamin E succinate for the entire experimental period (during heat and observation period) was necessary for this effect. R020-1724 in combination with vitamin E succinate was more effective in reducing the survival of heated cells than the individual agents. Although prostaglandin (PG) A2 did not increase cAMP level in melanoma cells, it decreased the survival of heated cells when present during heat treatment. Other forms of PG such as PGE1 and PGF2 alpha were ineffective. The combination of R020-1724 with two non-cAMP stimulating agents, PGA2 and vitamin E succinate, decreased the survival of heated cells by about 94% of control. These results suggest that the heat sensitivity of melanoma cells can be increased by cAMP-dependent and -independent mechanisms.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1995

Effect of vitamin E succinate on smokeless tobacco-induced production of nitric oxide by rat peritoneal macrophages and J774A.1 macrophage cells in culture.

Previous studies have shown that an aqueous smokeless tobacco extract when administered in a single oral dose to rats results in an enhanced induction of hepatic lipid peroxidation, hepatic DNA single strand breaks, and a marked increase in the urinary excretion of the lipid metabolites malondialdehyde, formaldehyde, acetaldehyde, and acetone. These observations strongly suggest that STE induces the production of reactive oxygen species. We have therefore examined the effects of STE in vivo in rats on the production of nitric oxide (NO) by isolated peritoneal exudate (macrophage) cells and when incubated with cultured J774A.1 macrophage cells. In both cases, a significant increase in NO production was observed. When the antioxidant vitamin E succinate was preadministered to rats, a marked decrease in NO production in response to STE by isolated peritoneal macrophages was observed. Similar results were observed when J774A.1 macrophages were cultured in the presence of vitamin E succinate and STE. When vitamin E succinate alone was cultured with macrophages, an increase in NO production was observed. A similar increase was observed when the vitamin E succinate was administered to rats, and NO production by isolated peritoneal macrophages was assessed. The results demonstrated that the increase in NO production by macrophages in response to vitamin E succinate was due to a succinate moiety. Taken together with previous studies, the results indicate that STE activates macrophages, which result in the production of reactive oxygen species. These reactive oxygen species may be responsible for tissue damaging effects including lipid peroxidation and DNA damage, which may be associated with the cytotoxicity and mutagenicity of smokeless tobacco products.

Animals↗
PubMed2005

Hepatic processing determines dual activity of alpha-tocopheryl succinate: a novel paradigm for a shift in biological activity due to pro-vitamin-to-vitamin conversion.

Redox-silent vitamin E analogues, represented by alpha-tocopheryl succinate, are potent anti-cancer drugs with potential secondary bioactivity due to their processing in vivo. Here we verified the hypothesis that hepatic processing of these agents determines the secondary effect. Mice were repeatedly injected with alpha-tocopheryl succinate, and their systemic and hepatic vein blood was assessed for alpha-tocopheryl succinate and its hydrolysis product, vitamin E (alpha-tocopherol). While levels of alpha-tocopherol doubled compared to control mice and alpha-tocopheryl succinate accumulated in the systemic blood, no alpha-tocopheryl succinate was detected in blood draining the liver. We conclude that hepatic processing endows compounds like alpha-tocopheryl succinate with a secondary, anti-oxidant/anti-inflammatory activity due to converting it to the redox-active alpha-tocopherol. Our finding epitomises a novel, general paradigm, according to which a drug can be converted in the liver into a product that has a different beneficial bioactivity.

Animals↗
PubMed1988

Evaluation of 99mtechnetium-dimercapto-succinic acid renal scans in experimental acute pyelonephritis in piglets.

We evaluated the sensitivity and specificity of 99mtechnetium-dimercapto-succinic acid renal scans in the detection and localization of experimental acute pyelonephritis in piglets. To create pyelonephritis vesicoureteral reflux of infected urine was surgically induced in 22 piglets. Nine animals were evaluated with a dimercapto-succinic acid renal scan at 1 week and 13 at 2 weeks. Autopsy and histopathological examination of the kidneys were performed subsequently. The location and extent of the inflammatory response found on histopathological examination were compared to dimercapto-succinic acid renal scan findings in a blinded fashion. Of the 22 kidneys subjected to vesicoureteral reflux 15 had positive histopathological findings of acute pyelonephritis, including 13 detected by the dimercapto-succinic acid renal scan findings. The 2 kidneys in which inflammation was not detected had only minimal grade I lesions and were grossly normal. There were no false positive scans in any of these kidneys. The sensitivity of the scan for detection of acute pyelonephritis in the kidneys subjected to reflux was 87 per cent and the specificity was 100 per cent. Furthermore, in these same kidneys the dimercapto-succinic acid renal scan findings correctly predicted the presence or absence of individual pyelonephritic lesions in 62 of 66 poles for an over-all agreement rate of 94 per cent. Thus, dimercapto-succinic acid renal cortical imaging is a highly sensitive and reliable imaging modality to detect and localize experimental acute pyelonephritis in piglets.

Acute Disease↗
PubMed1995

Hydrocortisone sodium succinate does not cross-react with aspirin in aspirin-sensitive patients with asthma.

BACKGROUND: Bronchospasm after intravenous hydrocortisone treatment has been reported in some patients with aspirin-sensitive respiratory disease. OBJECTIVE: This study was designed to determine the prevalence of sensitivity to hydrocortisone among patients with aspirin-sensitive respiratory disease. METHODS: We performed double-blind, placebo-controlled challenges with aspirin and 100 mg of hydrocortisone sodium succinate administered intravenously in 53 subjects. RESULTS: Forty-five of the 53 subjects (85%) undergoing oral aspirin challenge experienced respiratory reactions to aspirin. Forty-four of these 45 patients had neither naso-ocular, cutaneous, nor respiratory reactions to hydrocortisone sodium succinate. One aspirin-sensitive subject had bronchospasm and a naso-ocular reaction to hydrocortisone sodium succinate and a naso-ocular reaction with minimal bronchospasm to methylprednisolone sodium succinate. After desensitization to aspirin, and while receiving maintenance aspirin therapy, this subject again reacted to hydrocortisone sodium succinate with bronchospasm and naso-ocular reaction. CONCLUSION: We conclude that aspirin-sensitive patients with asthma are not preferentially sensitive to hydrocortisone and that hydrocortisone sodium succinate does not cross-react or cross-desensitize with aspirin.

Adult↗
PubMed1981

Bioavailability and clearance of chloramphenicol after intravenous chloramphenicol succinate.

Bioavailability of chloramphenicol and kinetics of chloramphenicol succinate and chloramphenicol were studied in 12 patients. Chloramphenicol succinate, 25 mg/kg, was injected intravenously every 6 hr over 0.5 to 1 hr. Both the drug and the prodrug were analyzed by high-pressure liquid chromatography. Bioabailability of chlorampenicol ranged from 0.55 to 0.92 and total, renal, and nonrenal clearance from 6.81 to 98.22, 2.54 to 26.90, and 3.73 to 87.38 ml/m2/min, while clearances of chloramphenicol succinate ranged from 84.75 to 916.00 28.40 to 312.00, and 26.06 to 760.93 ml/m2/min. Urinary recovery of chloramphenicol was 3% to 25% and that of chloramphenicol succinate was 7% to 45%. Mean apparent volumes of distribution were 0.71 l/kg for chloramphenicol and 2.10 l/kg for chloramphenicol succinate and elimination half-lifes were 4.03 and 2.65 hr, respecitively. There were relationships between patient age and clearance of both drugs. Incomplete bioavailability of chloramphenicol and the more than 10-fold variability in clearance of both chloramphenicol and chloramphenicol succinate explain the need for individualizing doses to achieve thrapeutic effect and minimize the risk to toxicity.

Adolescent↗
PubMed2006

alpha-Tocopheryl succinate induces apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 function.

Although the antitumor effect of alpha-tocopheryl succinate (vitamin E succinate) has been well demonstrated, its underlying mechanism remains elusive. This study provides evidence that inhibition of Bcl-xL/Bcl-2 function represents a major pathway whereby alpha-tocopheryl succinate mediates apoptosis induction in prostate cancer cells. In vitro data indicate that alpha-tocopheryl succinate was able to disrupt the binding of Bak BH3 peptide to Bcl-xL and Bcl-2 with IC50 of 26 microm, in line with its potency in antiproliferation. Treatment of PC-3 cells with this agent led to reduced association of Bcl-2 and Bcl-xL with Bak, leading to caspase-dependent apoptosis. Moreover, overexpression of Bcl-xL protected LNCaP cells from the apoptosis induction. This mechanistic finding provided a basis to develop potent Bcl-xL/Bcl-2 inhibitors. Docking of alpha-tocopheryl succinate into the Bak peptide-binding site indicates that it adopted a unique hairpin-shaped conformation for protein interactions. We rationalized that the hemisuccinate and the two proximal isopranyl units of the side chain played a crucial role in ligand anchoring and protein-ligand complex stabilization, respectively. However, exposure of the distal isopranyl unit to a polar environment might diminish the binding affinity of alpha-tocopheryl succinate. This premise was corroborated by a structure-activity analysis of a series of derivatives with truncated side chains and/or altered carboxyl terminus. This computer model predicted that the removal of the distal isopranyl unit from the side chain would improve binding affinity, leading to two agents with significantly higher potency in inhibiting Bak peptide binding and in suppressing prostate cancer cell proliferation.

Apoptosis↗
PubMed1999

Effect of charcoal hemoperfusion on clearance of cibenzoline succinate (cifenline) poisoning.

BACKGROUND: Management of cibenzoline succinate (cifenline) poisoning by symptomatic treatment is recommended because it has been reported cibenzoline succinate is not effectively removed by hemodialysis. The use of charcoal hemoperfusion for patients with cibenzoline succinate poisoning has not been reported previously. CASE REPORT: An 80-year-old woman with permanent right ventricular pacing was admitted to our hospital with general fatigue and clouding of consciousness. She had been receiving cibenzoline succinate for 1 month. The patient was clearly in shock on admission. Electrocardiogram showed a prolonged QRS and QTc interval and pacing failure. Hemodynamic failure, electrocardiographic abnormalities including pacing failure, and liver and renal dysfunction were compatible with cibenzoline succinate poisoning. Symptomatic treatment was provided. On day 4, charcoal hemoperfusion was initiated because of the development of hypoglycemia accompanied by liver and renal dysfunction. After charcoal hemoperfusion, the hypoglycemia, liver and renal dysfunction, prolonged QRS and QTc interval, and pacing threshold resolved. She was discharged on digoxin. We present a case of cibenzoline succinate poisoning treated with charcoal hemoperfusion which resulted in a rapid reduction of cibenzoline plasma concentrations with a significant clinical improvement.

Aged↗
PubMed1996

Alternative Oxidase Activity and the Ubiquinone Redox Level in Soybean Cotyledon and Arum Spadix Mitochondria during NADH and Succinate Oxidation.

In Arum and soybean (Glycine max L.) mitochondria, the dependence of the alternative oxidase activity on the redox level of ubiquinone, with NADH and succinate as substrates, was studied, using a voltametric procedure to measure the ubiquinone redox poise in the mitochondrial membrane. The results showed that when the enzyme was activated by pyruvate the relationship between the alternative oxidase rate and the redox state of the ubiquinone pool was the same for both NADH and succinate oxidations. In the absence of pyruvate the alternative oxidase had an apparent lower affinity for ubiquinol. This was more marked with NADH than with succinate and was possibly due to pyruvate production during succinate oxidation or to an activation of the alternative oxidase by succinate itself. In Arum spadix (unlike soybean cotyledon) mitochondria, succinate oxidation via the alternative oxidase maintained the ubiquinone pool in a partially reduced state (60%), whereas NADH oxidation kept it almost completely reduced. Previous data comparing mitochondria from thermogenic and nonthermogenic tissues have not examined the full range of ubiquinone redox levels in both tissues, leading to the suggestion that the activity of alternative oxidase for Arum was different from nonthermogenic tissues. When the complete range of redox states of ubiquinone is used and the oxidase is fully activated, the alternative oxidase from thermogenic tissue (Arum) behaves similarly to that of nonthermogenic tissue (soybean).

Journal Article↗
PubMed1980

Presence in Dry Pea Cotyledons of Soluble Succinate Dehydrogenase That Is Assembled into the Mitochondrial Inner Membrane during Seed Imbibition.

SUCCINATE DEHYDROGENASE (SUCCINATE: phenazine methosulfate oxidoreductase, EC 1.3.99.1) activity in crude mitochondrial fraction from pea (var. Alaska) cotyledons increased during seed imbibition to reach a maximum after about 12 hours. The increase was not inhibited by either cycloheximide or d(-)threo-chloramphenicol. The postmicrosomal fraction from dry cotyledons, but not that from fully imbibed ones, contained a soluble form of succinate dehydrogenase. The soluble enzyme was partially purified by ammonium sulfate fractionation and diethylaminoethyl-cellulose and Sepharose 6B column chromatography. The enzyme showed no succinate-coenzyme Q oxidoreductase activity and had a molecular mass of about 100,000 daltons. The soluble enzyme seemed to differ only slightly from succinate dehydrogenase solubilized from the mitochondrial inner membrane from fully imbibed cotyledons by a detergent. It is proposed that the soluble succinate dehydrogenase is associated with an inert mitochondrial inner membrane in dry cotyledons to form an active one during seed imbibition.

Journal Article↗
PubMed1986

Activation of glutamate apodecarboxylase by succinic semialdehyde and pyridoxamine 5'-phosphate.

Glutamate apodecarboxylase was activated by incubation with succinic semialdehyde and pyridoxamine 5'-phosphate. Activation required both compounds and was highly selective for succinic semialdehyde. Of 18 analogs tested, only glyoxylate, pyruvate, oxaloacetate, and 2-oxoglutarate activated the apoenzyme significantly, but much higher concentrations of these compounds than of succinic semialdehyde were required. In the presence of pyridoxamine 5'-phosphate, the concentration of succinic semialdehyde giving half-maximal activation of apoenzyme was 7 microM. In contrast, the Ki for succinic semialdehyde as a competitive inhibitor of glutamate decarboxylation was 1.2 mM, indicating that apoenzyme with bound pyridoxamine 5'-phosphate has a much higher affinity for succinic semialdehyde than does holoenzyme. The concentration of pyridoxamine 5'-phosphate giving half-maximal activation was 17 microM, which is more than an order of magnitude greater than the corresponding value for pyridoxal 5'-phosphate.

Apoenzymes↗
PubMed2006

Metoprolol succinate, a selective beta-adrenergic blocker, has no effect on insulin sensitivity.

Insulin resistance is a risk factor for cardiovascular disease. Therapies to lower blood pressure should not decrease insulin sensitivity. Some b-adrenergic blocking agents can have an adverse effect on insulin sensitivity. This study examined the effect of extended-release metoprolol succinate on insulin sensitivity. Nondiabetics with hypertension (N=30) were started on (or changed to) hydrochlorothiazide (HCTZ) 12.5 mg daily for 14 days. Patients with blood pressure>140/90 mm Hg while taking HCTZ alone underwent an insulin clamp procedure to quantify insulin sensitivity. Metoprolol succinate treatment was begun at 50 mg daily and titrated to a dose that lowered blood pressure to <140/90 mm Hg. Following 12 weeks of metoprolol succinate plus HCTZ therapy, the insulin clamp procedure was repeated. On metoprolol succinate plus HCTZ treatment, there were no significant changes in insulin clamp measures of insulin sensitivity. Plasma cholesterol and low-density lipoprotein cholesterol decreased significantly on metoprolol succinate plus HCTZ. When b-blocker therapy is considered, metoprolol succinate can be used to treat hypertension without adverse metabolic effects.

Adrenergic beta-Antagonists↗
PubMed1990

Growth, Respiration, and Polypeptide Patterns of Bradyrhizobium sp. (Arachis) Strain 3G4b20 from Succinate- or Oxygen-Limited Continuous Cultures.

Succinate- or oxygen-limited continuous cultures were used to study the influences of different concentrations of dissolved oxygen and ammonia on the growth, respiration, and polypeptide patterns of Bradyrhizobium sp. (Arachis) strain 3G4b20. During succinate-limited growth, molar growth yields on succinate (Y(succ)) ranged from 38.9 to 44.4 g (dry weight) of cells mol of succinate and were not greatly influenced by changes in dilution rates or changes in the oxygen concentrations that we tested. Succinate, malate, and fumarate induced the highest rates of oxygen uptake in all of the steady states in which the supply rates of (NH(4))(2)SO(4) ranged between 322 and 976 mumol h. However, the amino acids aspartate, asparagine, and glutamate could also be used as respiratory substrates, especially when the (NH(4))(2)SO(4) supply rate was decreased to 29 mumol h. Glutamine-dependent respiration was seen only when the (NH(4))(2)SO(4) supply rate was 29 mumol h and thus appears to be under tight ammonia control. Nitrogenase activity was detected only when the culture was switched from a succinate-limited steady state to an oxygen-limited steady state. Comparison of major silver-stained proteins from three steady states by two-dimensional gel electrophoresis revealed that nearly 60% were affected by oxygen and 24% were affected by ammonia. These data are consistent with reports that oxygen has a major regulatory role over developmental processes in Rhizobium sp. and Bradyrhizobium sp.

Journal Article↗
PubMed1999

Whey fermentation by anaerobiospirillum succiniciproducens for production of a succinate-based animal feed additive

Anaerobic fermentation processes for the production of a succinate-rich animal feed supplement from raw whey were investigated with batch, continuous, and variable-volume fed-batch cultures with Anaerobiospirillum succiniciproducens. The highest succinate yield, 90%, was obtained in a variable-volume fed-batch process in comparison to 80% yield in a batch cultivation mode. In continuous culture, succinate productivity was 3 g/liter/h, and the yield was 60%. Under conditions of excess CO2, more than 90% of the whey-lactose was consumed, with an end product ratio of 4 succinate to 1 acetate. Under conditions of limited CO2, lactose was only partially consumed and lactate was the major end product, with lower levels of ethanol, succinate, and acetate. When the succinic acid in this fermentation product was added to rumen fluid, it was completely consumed by a mixed rumen population and was 90% decarboxylated to propionate on a molar basis. The whey fermentation product formed under excess CO2, which contained mainly organic acids and cells, could potentially be used as an animal feed supplement.

Journal Article↗
PubMedDate not supplied

Clinical pharmacokinetics of chloramphenicol and chloramphenicol succinate.

In recent years there has been a renewal of interest in chloramphenicol, predominantly because of the emergence of ampicillin-resistant Haemophilus influenzae, the leading cause of bacterial meningitis in infants and children. Three preparations of chloramphenicol are most commonly used in clinical practice: a crystalline powder for oral administration, a palmitate ester for oral administration as a suspension, and a succinate ester for parenteral administration. Both esters are inactive, requiring hydrolysis to chloramphenicol for anti-bacterial activity. The palmitate ester is hydrolysed in the small intestine to active chloramphenicol prior to absorption. Chloramphenicol succinate acts as a prodrug, being converted to active chloramphenicol while it is circulating in the body. Various assays have been developed to determine the concentration of chloramphenicol in biological fluids. Of these, high-performance liquid chromatographic and radioenzymatic assays are accurate, precise, specific, and have excellent sensitivities for chloramphenicol. They are rapid and have made therapeutic drug monitoring practical for chloramphenicol. The bioavailability of oral crystalline chloramphenicol and chloramphenicol palmitate is approximately 80%. The time for peak plasma concentrations is dependent on particle size and correlates with in vitro dissolution and deaggregation rates. The bioavailability of chloramphenicol after intravenous administration of the succinate ester averages approximately 70%, but the range is quite variable. Incomplete bioavailability is the result of renal excretion of unchanged chloramphenicol succinate prior to it being hydrolysed to active chloramphenicol. Plasma protein binding of chloramphenicol is approximately 60% in healthy adults. The drug is extensively distributed to many tissues and body fluids, including cerebrospinal fluid and breast milk, and it crosses the placenta. Reported mean values for the apparent volume of distribution range from 0.6 to 1.0 L/kg. Most of a chloramphenicol dose is metabolised by the liver to inactive products, the chief metabolite being a glucuronide conjugate; only 5 to 15% of chloramphenicol is excreted unchanged in the urine. The elimination half-life is approximately 4 hours. Inaccurate determinations of the pharmacokinetic parameters may result by incorrectly assuming rapid and complete hydrolysis of chloramphenicol succinate. The pharmacokinetics of chloramphenicol succinate have been described by a 2-compartment model. The reported values for the apparent volume of distribution range from 0.2 to 3.1 L/kg.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗