In a dose-dependent manner, citric acid (0–12.5 mM; 24 hours) exhibits antiproliferative activity [3]. In G2/M and S phases, citric acid (12.5 mM; 72 h) dose-dependently induces apoptosis and cell cycle arrest [3]. The expression of FAS, BAX, BID, AIF, EndoG, cytochrome c, PARP, GADD153, GRP78, and caspase-3, -8, and -9 was increased and that of BCL-2 and BCL - Xl was decreased when exposed to 12.5 mM of citric acid for 48 hours[3].

Citric acid (120, 240, and 480 mg/kg; intraperitoneal injection) can significantly reduce GSH-Px activity and induce an increase in MDA (malondialdehyde) levels in mouse livers [1]. Citric acid (120, 240, and 480 mg/kg; i.p.) promotes apoptosis by raising caspase-3 activity in mouse hepatocytes in a dose-dependent manner [1]. ?Citric acid (120, 240, and 480 mg/kg; intraperitoneal injection; once weekly for 3 weeks) produces nephrotoxicity in mice [2].

Cell Viability Assay[3]
Cell Types: HaCaT Cell
Tested Concentrations: 0, 2.5, 5, 7.5, 10, 12.5 mM
Incubation Duration: 24 hrs (hours)
Experimental Results: Inhibition of cell viability in a dose-dependent manner.

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Cytotoxicity assay [3]
Cell Types: HaCaT Cell
Tested Concentrations: 12.5 mM
Incubation Duration: 0, 12, 24, 48, 72 h
Experimental Results: Induced apoptosis and cell cycle arrest in G2/M phase and S in a dose-dependent manner Expect.

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Western Blot Analysis[3]
Cell Types: HaCaT Cell
Tested Concentrations: 12.5 mM
Incubation Duration: 12, 24, 48 hrs (hours)
Experimental Results: Increased expression of FAS, BAX, BID, AIF, EndoG, cytochrome c, PARP, GADD153, GRP78 and caspase -3, -8, -9, and BCL-2 and BCL-X1 were diminished.

Animal/Disease Models: 20 g male Kunming mice [2]
Doses: 120, 240, 480 mg/kg
Route of Administration: intraperitoneal (ip) injection; once a week for 3 weeks.
Experimental Results: The activities of T-SOD and GSH-Px in the treatment group diminished with the increase of citric acid dose, the activity of NOS demonstrated an increasing trend, and the contents of H2O2 and MDA gradually diminished.

Absorption, Distribution and Excretion
/A portion/ of the circulating (mainly metabolic but also ingested) citric acid is excreted in urine, with 24-hour urine reference values between 1.5 and 3.68 mmol, corresponding to 0.29-0.71 g citric acid excreted per person per day.

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Metabolism / Metabolites
Citric acid is a normal metabolite and an intermediate in cellular oxidative metabolism ... The acid is formed in the mitochondrion after condensation of acetate with oxaloacetate. The six-carbon acid is then successively degraded to a series of four-carbon acids, effectively accomplishing oxidation of acetate in the cell.
In human (as well as in animal and plant) physiology, citric acid is a very common intermediate in one of the central biochemical cycles, the Krebs or tricarboxylic acid cycle, which takes place in every cell. It completes the breakdown of pyruvate formed from glucose through glycolysis, thereby liberating carbon dioxide and a further four hydrogen atoms which are picked up by electron transport molecules. Thus, in man approximately 2 kg of citric acid are formed and metabolised every day. This physiological pathway is very well developed and capable of processing very high amounts of citric acid as long as it occurs in low concentrations.
Citric acid in reaction with enzyme citratase /citrate lyase/ yields oxaloacetic acid & acetic acid.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No data are available on cellulose and citric acid use during breastfeeding. However, the drug is not absorbed from the gastrointestinal tract, so it cannot enter the breastmilk. Cellulose and citric acid is acceptable to use during breastfeeding.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Interactions
... Citric acid aerosol inhalation caused decreases in dynamic respiratory compliance and forced expiratory volume in 0.1 s (FEV0.1). This airway constriction was significantly attenuated by MK-886, mepyramine, cromolyn sodium, and compound 48/80, but not by either methysergide or indomethacin. Both LTC4 and histamine infusion significantly increased the magnitude of citric acid-induced airway constriction in compound 48/80-pretreated guinea pigs. Citric acid inhalation caused significant increase in histamine level in the bronchoalveolar lavage sample, which was significantly suppressed by compound 48/80.
The relative efficacy of citric, malic, malonic, oxalic and succinic acids, and deferoxamine mesylate on the toxicity, distribution and excretion in mice exposed to aluminum were compared. Chelating agents were administered ip at a dose equal to one-fourth of their respective LD50. To determine the effect of the various chelators on the toxicity of aluminum, various doses of aluminum nitrate (938-3188 mg/kg) were administered ip, followed by one of the chelators. Survival was recorded at the end of 14 days. ... Malic acid and deferoxamine mesylate were the most effective in increasing the urinary excretion of aluminum. Citric acid was the most effective in increasing the fecal excretion of aluminum. Malonic, oxalic and succinic acids had no overall beneficial effects. Citric acid would appear to be the most effective agent of those tested in the prevention of acute aluminium intoxication.
... When aluminum hydroxide and citric acid (133 mg Al/kg and 62 mg/kg, respectively) were simultaneously given orally to mice, fetal skeletal development defects resulted.
The primary purpose of this study was to determine the relative usefulness of various measures to monitor body aluminum burden in weanling rats fed various amounts of aluminum (0.39 umol aluminum/g diet for 29 days, approximately 40 umol aluminum/g diet with or without citrate for 29 days and approximately 100 umol aluminum/g diet with citrate for 12 or 29 days) or injected ip with graded doses of aluminum (0.01, 4.6, 11.8, 23.5 or 94 umol aluminum). Twenty four hours prior to sacrifice, all rats were injected ip with either desferrioxamine (75 mg) or buffer. All seven indices of aluminum exposure monitored (eg: tibia, liver, kidney and serum aluminum concn; changes in serum aluminum concn in response to desferrioxamine; urinary aluminum excretion with and without desferrioxamine treatment) were highly (p< 0.001) correlated to parenteral aluminum exposure. Ingestion of citrate had small but significant effects on aluminum retention. /Citrate/
For more Interactions (Complete) data for CITRIC ACID (7 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 3000 mg/kg; 12000 mg/kg; 11700 mg/kg /observed in separate experiments/
LD50 Rat oral 6730 mg/kg
LD50 Mouse iv 42 mg/kg /From table/
LD50 Mouse oral 5040 mg/kg /From table/
For more Non-Human Toxicity Values (Complete) data for CITRIC ACID (10 total), please visit the HSDB record page.

[1]. Study on injury effect of food additive citric acid on liver tissue in mice. Cytotechnology. 2014 Mar;66(2):275-82.

[2]. Chen X, Lv Q, Liu Y, Deng W. Effects of the food additive, citric acid, on kidney cells of mice. Biotech Histochem. 2015 Jan;90(1):38-44.

[3]. Citric acid induces cell-cycle arrest and apoptosis of human immortalized keratinocyte cell line (HaCaT) via caspase- and mitochondrial-dependent signaling pathways. Anticancer Res. 2013 Oct;33(10):4411-20.

Therapeutic Uses
Mesh Heading: Anticoagulants, chelating Agents
/EXPL THER/ Regional citrate anticoagulation (RCA) is an effective form of anticoagulation for continuous renal replacement therapy (CRRT) in patients with contraindications to heparin. Its use has been very limited, possibly because of the need for special infusion solutions and difficult monitoring of the metabolic effects./The objective of this study was/ to investigate the safety and the feasibility of an RCA method for continuous veno-venous hemofiltration (CVVH) using commercially available replacement fluid. We evaluated 11 patients at high risk of bleeding, requiring CVVH. RCA was performed using commercially available replacement fluid solutions to maintain adequate acid-base balance. We adjusted the rate of citrate infusion to achieve a post-filter ionized calcium concentration [iCa] <0.4 mmol/L when blood flow was <250 mL/min, or <0.6 mmol/L when blood flow was >250 mL/min. When needed, we infused calcium gluconate to maintain systemic plasma [iCa] within the normal range. Twenty-nine filters ran for a total of 965.5 hr. Average filter life was 33.6+/-20.5 hr. Asymptomatic hypocalcemia was detected in 6.9% of all samples. No [iCa] values <0.9 mmol/L were observed. Hypercalcemia (1.39+/-0.05 mmol/L) occurred in 2.5% of all samples. /The authors/ observed hypernatremia (threshold 153 mmol/L) and alkalosis (threshold 7.51) in only 9.3% and 9.4% respectively of all samples, mostly concomitantly. No patient showed any signs of citrate toxicity. /They/ developed a protocol for RCA during CVVH using commercially available replacement fluid that proved safe, flexible and applicable in an Intensive Care Unit (ICU) setting.
It has ... been used to dissolve urinary bladder calculi, & as mild astringent.
Citrate ... of ... value in alleviation of chronic metabolic acidosis ... from chronic renal insufficiency or syndrome of renal tubular acidosis ... usually prescribed in form of sodium citrate and citric acid soln, USP ...
Potassium citrate, up to 10 g daily, has been used as a potassium supplement; the potassium and sodium salts have been used, in similar dosages, as mild diuretics in humans.

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Drug Warnings
A study of abdominal pain and severity of other side effects attributed to Picolax, a combination of citric acid, magnesium oxide and sodium picosulfate, was conducted among 267 patients, 55 of whom had inflammatory bowel disease, all of whom were given a full single dose of Picolax as preparation for radiology or endoscopy. The frequency of increased abdominal pain and severe side effects after Picolax administration was similar in the patients with inflammatory bowel disease and the patients with other colonic disorders. None of the patients with iron deficiency in whom investigations had yielded negative results reported severe side effects; this was significantly different from the proportion reporting severe side effects among the patients with inflammatory bowel disease, the irritable bowel syndrome and diverticular disease. The increase in the mean number of stools/24 hr after Picolax was lower in the patients with inflammatory bowel disease than in the other diagnostic groups. On review 2-4 wk after examination none of the patients with inflammatory bowel disease reported deterioration in their symptoms.
Following the occurrence of aluminum encephalopathy in four patients with chronic renal failure, 34 azotemic patients seen during the same year and five volunteers who took varying combinations of aluminum hydroxide and an alkalinizing citrate (Shohl's) solution were studied. It was found that the four encephalopathic cases were older than the 34 azotemic patients (68 years + or - 14 standard deviation, versus 50 + or - 13, p< 0.05), had a higher mean serum aluminum value (727 ug/l + or - 320 versus 92 + or - 73, p< 0.005), had taken more aluminum hydroxide (5 g/day + or - 0.9 versus 1.6 + or - 1.8, p< 0.01), and more Shohl's solution (64 ml/day + or - 19 versus 20 + or - 29, p< 0.01). In all 38 patients the serum aluminum values correlated directly with age (p=0.01), aluminum hydroxide (p=0.001) and concomitant citrate intake (p=0.004). In the five healthy volunteers the 24 hr urinary aluminum excretion increased from a baseline of 22 ug + or - 19 standard deviation to 167 + or - 109 (p=0.05) during aluminum hydroxide intake, rising to 580 + or - 267 (p=0.01) during the simultaneous intake of citrate and aluminum hydroxide. Corresponding serum aluminum values were 11 ug/l + or - 2 standard deviation, 44 + or - 34 (p= 0.1), and 98 + or - 58 (p<0.05). Thus citrate seems to enhance aluminum absorption and may cause encephalopathy in patients with chronic renal failure, especially the elderly.

C6H8O7

192.1235

192.027

77-92-9

Lithium citrate tetrahydrate;6080-58-6;Citric acid triammonium;3458-72-8;Sodium citrate dihydrate;6132-04-3;Citric acid trisodium;68-04-2;Citric acid monohydrate;5949-29-1;Ferric citrate;3522-50-7;Citric acid-d4;147664-83-3;Citric acid-13C6;287389-42-8;Hydroxycitric acid tripotassium hydrate;6100-05-6;Citric acid-13C3;302912-06-7

311

White to off-white solid powder

1.8±0.1 g/cm3

309.6±42.0 °C at 760 mmHg

153-159 °C(lit.)

155.2±24.4 °C

0.0±1.5 mmHg at 25°C

1.575

-1.72

4

7

5

13

227

0

KRKNYBCHXYNGOX-UHFFFAOYSA-N

InChI=1S/C6H8O7/c7-3(8)1-6(13,5(11)12)2-4(9)10/h13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)

2-hydroxypropane-1,2,3-tricarboxylic acid

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)

H2O : ~100 mg/mL (~520.51 mM)
DMSO : ~100 mg/mL (~520.51 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (13.01 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (13.01 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (13.01 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (520.51 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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