Microbial Metabolite; Endogenous Metabolite; Flavoring Agents; Alters several flavor and/or taste characteristics; Food additives; Fragrance Ingredients; Cosmetics -> Buffering; Environmental transformation -> Pesticide transformation products (metabolite, successor)

The present study hypothesized that fumaric acid and succinic acid may exhibit therapeutic effects on gestational hypertension. During pregnancy, estrogen upregulates ten-eleven translocation 1 (TET1) expression, which subsequently increases calcium-activated potassium channel subunit β1 (KCNMB1) expression. KCNMB1 is associated with hypertension. Fumaric acid and succinic acid are understood to inhibit TET. Therefore, the present study investigated whether fumaric acid and succinic acid exhibit therapeutic effects on gestational hypertension and whether these effects are mediated by TET1 and KCNMB1. Nω-Nitro-L-arginine methyl ester hydrochloride was injected into rats to establish a gestational hypertension model. Dimethyl fumarate (DMF) and succinic acid were administrated into rats to treat gestational hypertension. Rats were divided into five groups: i) Control; ii) model; iii) DMF; iv) succinic acid; and v) DMF + succinic acid. Blood pressure was monitored by a noninvasive meter and urinary protein was determined using a urinary protein kit. Placenta pathology was examined by hematoxylin-eosin staining. Compared with the control group, urinary protein and blood pressure in the model group increased significantly. The placental cells in the control group were arranged orderly. However, in the model group, decidual cellular edema of placenta and vacuolar degeneration were observed, and the intervascular membrane was markedly thicker with plenty of fibrin deposition. These results indicate successful establishment of a gestational hypertension model. However, compared with the model group, urinary protein, blood pressure, edema, vacuoles and fibrin deposition were markedly reduced in the DMF, succinic acid and DMF + succinic acid groups. mRNA and protein levels of TET1 and KCNMB1 in placenta were evaluated by immunohistochemical analysis, reverse transcription-quantitative polymerase chain reaction and western blotting. The TET1 and KCNMB1 levels in the model group were markedly increased compared with those in the control group. However, compared with the model group, the expression levels were markedly downregulated in the DMF, succinic acid and DMF + succinic acid groups. In conclusion, fumaric acid and succinic acid may treat gestational hypertension by downregulating the expression of KCNMB1 and TET1[3].

The percentage that enters the open arm and the amount of time spent in the open arm are both increased by sodium succinate (3.0 or 6.0 mg/kg, PO) [1]. In comparison to the vehicle, succinic acid (3.0, 6.0, and 12.0 mg/kg, IP) significantly increased food intake in less than five minutes [1]. The rat colon was injected with 100 mM sodium succinate, which dramatically decreased the size of the crypt and hindered colonocyte growth [2].

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Microbial breakdown of carbohydrates in the large intestine mainly produces short-chain fatty acids (SCFA). SCFA stimulate epithelial cell proliferation of the digestive tract in vivo. Succinic acid sometimes accumulates in the colonic lumen. However, the effect of succinic acid on colonic epithelial cell proliferation is unknown. Thus, we planned to clarify the influence of succinic acid on colonic epithelial cell proliferation in vivo. We continuously administered infusate with or without succinic acid (100 mM) into the distal colon of rats for 6 d and measured accumulated mitosis per crypt of distal colon of these rats. Succinic acid infused into rat colons significantly inhibited colonic cell proliferation and reduced crypt size. These results clearly indicated the inhibitory effects of succinic acid on colonic epithelial cell proliferation in vivo[2].

The putative anxiolytic activity of succinic acid was examined in male mice by using a number of experimental paradigms of anxiety and compared with that of the known anxiolytic compound diazepam. Use of the elevated plus-maze test revealed that diazepam (1.0, 2.0 and 4.0 mg/kg, PO) or succinic acid (3.0 or 6.0 mg/kg, PO) increased the percentage of entries into open arms and of time spent on open arms. In novel food consumption test, succinic acid (3.0, 6.0, and 12.0 mg/kg, IP) caused significant increases in food intake during 5 min when compared with the vehicle. In the stress-induced hyperthermia test, 40 min after drug administration rectal temperature was measured, succinic acid at dose of 1.5 mg/kg, inhibited stress-induced hyperthermia. Thus, these findings indicated that, in contrast with diazepam, succinic acid exhibits anxiolytic-like effect.[1]

Absorption, Distribution, and Excretion
Succinic acid is normally present in human urine (1.9-8.8 mg/L).
Metabolism/Metabolites
Succinic acid is a normal intermediate metabolite and a component of the citric acid cycle. When administered to animals, it is readily metabolized, but in large doses, some succinic acid may be excreted unchanged in the urine.
Succinic acid can be oxidized to fumarate by succinate dehydrogenase.
Pesticide Transformation
Succinic acid is a known environmental transformation product of sulfadiazine.
Succinic acid is a known environmental transformation product of linuron.

Toxicity Overview
Succinate inhibits the activity of α-ketoglutarate-dependent oxygenases (KDMs) and TET family 5-methylcytosine (5mC) hydroxylases. Succinate also mediates allosteric inhibition of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs). Inhibition of HIF PHDs activates HIF-mediated pseudohypoxia responses, while inhibition of KDMs and TET family 5mC hydroxylases leads to epigenetic alterations, ultimately resulting in cancer. Succinylation of KEAP1 in FH deficiency leads to constitutive activation of NRF2-mediated antioxidant defense pathways, creating a reducing environment that promotes cell proliferation. Succinylation of the Krebs cycle enzyme Aco2 impairs aconitase activity in Fh1-deficient MEF cells. Succinylation also leads to irreversible inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

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Health Effects
Succinate can irritate the skin at acute doses or exposure. Long-term high doses of succinate can lead to succinylation or succinification of various enzymes. A partial deficiency of succinate dehydrogenase in skeletal muscle (15% to 50% of normal reference enzyme activity) results in elevated succinate levels and causes mitochondrial myopathy, leading to a variety of symptoms such as brain involvement, cardiomyopathy, and/or exercise intolerance.

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Routes of Exposure
Eye contact, inhalation, ingestion.

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Symptoms
Acute exposure: Clinical symptoms of acute poisoning include weakness and diarrhea.

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Adverse Reactions
Neurotoxins - Other Central Nervous System Neurotoxins

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Toxicity Data
Acute Oral Toxicity (LD50): 2260 mg/kg [Rat].

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Treatment
Eyes: Rinse open eyes with running water for several minutes. Ingestion: Do not induce vomiting. Rinse mouth with water (never feed anything to an unconscious person). Seek immediate medical attention. Skin: Immediately rinse affected area with cold water for at least 15 minutes, then wash thoroughly with soap and water. If necessary, the patient should shower and change contaminated clothing and shoes, and must then seek medical attention. Inhalation: Provide fresh air. If necessary, perform artificial respiration.

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Human Toxicity Excerpt
/Other Toxicity Information/ Many aliphatic dicarboxylic acids have major irritant effects, especially in concentrated solutions or dust—sensitization is rare. /Aliphatic Dicarboxylic Acids/ International Labour Organization. Encyclopedia of Occupational Health and Safety, Volumes 1 and 2. New York: McGraw-Hill Books, 1971, p. 30.

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Non-Human Toxicity Excerpt/Laboratory Animals: Acute Exposure/Succinic acid is mildly irritating to the skin and strongly irritating to the eyes of rats. A 15% solution of 750 micrograms of succinic acid caused severe damage to the eyes of rabbits. Clinical symptoms of acute poisoning in rats were weakness and diarrhea.
/Laboratory Animals: Acute Exposure/ High-dose intravenous administration of sodium succinate can cause vomiting and diarrhea in cats…
/Experimental Animals: Subchronic or Pre-chronic Exposure/ Rats/Fischer (F344) Males and Females, 10 rats per group/Exposed to/ 13 weeks, free access to/0, 0.3, 0.6, 1.25, 2.5, 5, 10% sodium succinate (100.2% purity). …The weight gain of rats in the 10% group was severely inhibited, and all rats in this group died within the first 4 weeks of the experiment. However, all rats in the other dose groups survived to the end of the experiment. Inhibition of weight gain was observed at concentrations ≥2.5%. Water intake was very low in the highest dose group, although water intake was higher in the 5% group than in the other groups. No dose-related specific changes were observed in any parameters of hematological and biochemical assays. Rats that died during the experiment were severely emaciated. However, despite the observation of organ atrophy, histopathological examination did not reveal any toxic lesions caused by the test substance in any organs of these rats. No specific lesions were observed in histological examination of any other experimental groups. Based on the weight loss inhibition, the maximum tolerated dose of sodium monosuccinate in drinking water was determined to be approximately 2-2.5%.

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Non-human toxicity values
Oral LD50 in rats: 2260 mg/kg

[1]. Chen SW, Xin Q, Kong WX, Min L, Li JF. Anxiolytic-like effect of succinic acid in mice. Life Sci. 2003 Nov 7;73(25):3257-64.

[2]. Inhibitory effect of succinic acid on epithelial cell proliferation of colonic mucosa in rats. J Nutr Sci Vitaminol (Tokyo). 2007 Aug;53(4):377-9.

[3]. Fumaric acid and succinic acid treat gestational hypertension by downregulating the expression of KCNMB1 and TET1. Exp Ther Med. 2021 Oct;22(4):1072.

Anhydrous sodium succinate is the disodium salt of succinic acid. Sodium succinate hexahydrate is used as a topical ingredient in medications for the treatment of cataracts. It contains the succinate ion (2-).
See also: Succinic acid (with active moiety).

C4H6O4.NA

141.016

14047-56-4

9020

Typically exists as solid at room temperature

158ºC at 760mmHg

0.0165mmHg at 25°C

0

4

1

10

81.6

0

[NaH].OC(CCC(=O)O)=O

ZDQYSKICYIVCPN-UHFFFAOYSA-L

InChI=1S/C4H6O4.2Na/c5-3(6)1-2-4(7)8;;/h1-2H2,(H,5,6)(H,7,8);;/q;2*+1/p-2

disodium;butanedioate

Butanedioic acid, sodium salt; 14047-56-4; Succinic acid, sodium salt; EINECS 237-884-4; Butanedioic acid, sodium salt (1:?); sodium;butanedioate;hydron; SCHEMBL24441; DUMIASQJCCZABP-UHFFFAOYSA-N

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)