Calcium-D-Glucarate

Last Updated: September 28, 2022

Calcium-D-Glucarate is a β-glucuronidase inhibitor that promotes the excretion of any molecule in a specific detoxification pathway. It has shown efficacy at very high (impractical) oral doses in reducing cancer induced by these compounds, but may also reduce all steroid hormones as well.

dosageDosage

Calcium-D-Glucarate is most often used for



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1.

Sources and Structure

1.1

Sources

Calcium-D-Glucarate is a calcium salt of the molecule known as D-Glucaric acid (also known as Saccharic acid),[1] an endogenously produced acid via D-glucuronic acid[2] that also appears to be found in fruit and vegetable food products with high levels in oranges, apples, grapefruit, and cruciferous vegetables.[3] As D-glucaric acid is the main bioactive, any dietary supplement conferring it can be of similar benefit (including potassium hydrogen D-glucarate[4]).

It is thought that glucaric acid is chemoprotective, and it has been noted that in cohorts of smokers with indicators of DNA damage (K-ras mutations) that circulating glucaric acid is 34% lower.[5]

Glucaric acid, supplemented via its calcium salt (Calcium-D-Glucarate), is thought to be a chemoprotective and anti-toxin compound

Specific concentrations of glucaric acid found in food products include:

  • Peeled oranges at 4.63+/-0.58mg/100g[3]
  • Carrots at 2.45+/-0.32mg/100g[3]
  • Spinach at 1.58+/-0.35mg/100g[3]
  • Apples at 1.57+/-0.09mg/100g[3]
  • Broccoli at 1.32+/-0.23mg/100g[3]
  • Alfalfa sprouts at 0.82+/-0.06mg/100g[3]
  • Peeled potatoes at 0.74+/-0.08mg/100g[3]

Oranges appear to be the highest known source, followed by applies and broccoli. Admittedly, however, not many food products appear to have been tested for the presence of glucaric acid salts

1.2

Structure

As calcium-D-glucarate is a calcium salt of D-glucaric acid, it is simply the structure of each individual molecule. Other molecules that also confer D-glucarate (such as potassium hydrogen D-glucarate) confer similar properties to the body.

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1.3

Dosing

It has been noted by some authors that dietary concentrations of glucaric acid are likely not high enough to confer sufficient biological activity.[3]

A single dose of 4.5mmol/kg (1.1g/kg) calcium-D-glucarate has been confirmed to inhibit β-glucuronidase in lung (37%), liver (44%), serum (57%), and intestines (39%).[6] Serum activity tends to correlate tissue activity somewhat,[7] and oral calcium-D-glucarate appears to be active on the enzyme for about 5 hours.[8][1]

It has been noted that increasing the concentration of Calcium-D-Glucarate from 4% of the rat diet to 10% doesn't modify intake of food but fails to provide further inhibition of β-glucuronidase (suggesting a limit cap at 4% of intake)[6][3] and in general there is dose response but it is significantly attenuated after 2% of the diet (2,4, and 10% are not significantly different, but all better than 1%).[6]

4% of the diet for 2 weeks in rats has shown inhibitory effects of 54-70% in the intestinal tract[3] and 2% of the diet has reduced serum β-glucuronidase approximately 50%.[6]

Although technically dose-dependent, the dose where there are not significant additional returns in rats is 2% of the diet (converted to human doses based on average food consumption and body weight of around 25g/250g, this is 2,000mg/kg bodyweight or a human dose of 320mg/kg). Due to this already being much higher than the recommended dose in humans, an 'upper limit' is likely not a concern

2.

Pharmacology

2.1

Metabolism

Calcium-D-Glucarate is hydrolyzed into free calcium and D-glucaric acid upon introduction to an acidic environment (stomach acid)[9][10] and D-glucaric acid is then metabolized into one of two metabolites; D-glucaro-1,4-lactone (30% of ingested D-glucaric acid) or D-glucaro-6,3-lactone (also 30%) while 40% remains as D-glucaric acid.[1] Elsewhere, slightly lower numbers have been reported (with D-glucaro-1,4-lactone consisting of 17-22% of total D-glucaric acid in the bile and urine[11])

If needed, D-glucaro-1,4-lactone can be produced in a cellular environment from oxidative changes on D-glucaric acid.[2]

Glucaric acid is metabolized via stomach acid partly into one of two metabolites, the main bioactive D-glucaro-1,4-lactone and then an equal amount of D-glucaro-6,3-lactone while some D-glucaric acid remains in its parent form

2.2

Glucuronidation

Glucuronidation is a process by which usually a molecule (usually hydrophobic) is attached to a glucuronide group, usually by the enzyme glucuronosyltransferase. The addition of a glucuronide group via glucuronidation signals the molecule for excretion from the body via the kidneys as it makes the molecule more water soluble; it is one of the major pathways of detoxification in the body.[10]

There is an opposite reaction where a glucuronidated molecule has the glucuronide group removed, and this reaction is mediated by the enzyme β-glucuronidase; this enzyme is the molecular target of D-glucaric acid's metabolite Glucaro-1,4-lactone, which is a β-glucuronidase inhibitor with a Ki of 1.6µM.[3]

Inhibition of β-glucuronidase from glucaro-1,4-lactone prevents removal of glucuronide groups and facilitates their removal from the body.

Glucuronidation is a process by which a glucuronide group is added to a molecule and signals for said molecule to be excreted via the kidneys (urinated). D-Glucaric acid, via its metabolite, inhibits the removal of the glucuronide group and preserves/promotes excretion of any molecule that is subject to glucuronidation

Endogenous substances that are known to be glucuronidated (and thus can potentially have their excretion enhanced by D-glucaric acid supplementation) include steroid hormones,[6] and bilirubin.[10]

Exogenous compounds that are sometimes referred to as 'toxins' that can be glucuronidated include benzo(a)pyrene compounds, which are commonly found in cooked meat products (usually those that are smoked and charred).[12][13] Polyaromatic hydrocarbons (PAHs) may also be glucuronidated.[14]

Accelerating the process of glucuronidation can accelerate the excretion of bilirubin and steroid hormones, and may increase the rate of elimination of various meat-based carcinogens produced in cooking

β-glucuronidase also has its activity suppressed by caloric restriction.[15]

2.3

Excretion

Glucarate and Glucaro-1,4-lactone are both excreted in the urine[16] and due to being synthesized in the body are normally excreted in the urine regardless of supplementation status.[17]

Glucaric acid is excreted in the urine either as parent glucaric acid or as its metabolites

3.

Interactions with Hormones

3.1

Steroid Hormones

In rats given 10% of the diet as calcium-D-glucarate, serum estrogen has been noted to be reduced 23% relative to control.[6] Although 10% of the diet is approximately 1,000mg/kg (estimated human equivalent based upon body weight conversions), 200mg/kg should be somewhat similarly effective (see dosing section).

Although no studies have directly investigated the excretion of testosterone, it is known to be glucuronidated[18][19] and inhibition of glucuronidation is a mechanism by which green tea catechins are thought to increase testosterone in the body;[20] it is wholly plausible that serum testosterone is reduced following glucaric acid supplementation, but currently not demonstrated.

Furthermore, urinary 17-ketosteroids (collective term for DHEA, androstenedione, androsterone, and estrone) appear to be increased approximately 200% following 2 days on a diet containing 10% calcium-D-glucarate in rats, but is attenuated to 50% after two weeks.[6]

Urinary excretion of all steroid hormones appears to be increased following exposure to D-glucaric acid at high oral doses, since these steroid hormones themselves are subject to glucuronidation

4.

Interactions with Cancer Metabolism

4.1

Toxin-induced Carcinogenesis

Calcium-D-Glucarate is thought to confer protection against breast cancer, at least in part via the reduction of estrogen levels[8] but mostly due to augmenting the excretion of pro-carcinogenic drugs that are subject to glucuronidation.

Protection against one particular research toxin (7,12-DMBA) has been noted with acute usage of 9mmol/kg calcium-D-glucarate (4.5mmol 3 hours prior to and another dose 30 minutes prior to DMBA injections) which reduced tumor occurrence from 100% to 30%[6] and studies with more chronic loading have noted benefit with dietary supplementation of 75mmol/kg (of the diet, 5.37mmol/kg bodyweight and 213mg/kg human equivalent).[21][6] This protective effect extends beyond breast cancer and is able to attenuate skin cancer with either calcium-D-glucarate itself[22] or the main bioactive metabolite[23] (skin cancer is known to be able to be induced by DMBA[24]) and may also extend to DMBA induced oral cancers.[25]

Protective effects have also been noted in colon cancer (with potassium hydrogen glucaric acid 140mmol/kg feed,[26] but as potassium hydrogen carbonate was inactive the bioactive appears to be glucaric acid) induced by the toxin azoxymethane, which normally induces activity of β-glucuronidase[27] and inhibitors in general have antitumor effects.[28] This study noted that tumor size and multiplicity was reduced to approximately 60% of control.[26]

A two week delay following introduction of the toxin appears to still be effective (although to a lesser degree) and acute usage of calcium-D-glucarate prior to exposure to the toxin is also effective.[6]

Glucaric acid, via increasing excretion of toxin that are normally subject to this particular detoxification pathway (glucuronidation), can reduce the time a toxin can act in the body and thus reduce the overall cancer causing effects of the toxin. This has been noted in rats repeatedly, but albeit using remarkably high doses (human equivalent is about 200mg/kg bodyweight minimum)

Glucaric acid does not have any inherent anti-cancer effects and may not protect against toxins that are not subject to glucuronidation. The anticancer effects of glucaric acid appear to be very specific to increasing drug excretion rates, and organic cancer (produced from inflammation and oxidation) may not be protected against with glucaric acid supplementation

5.

Nutrient-Nutrient Interactions

5.1

Resveratrol

A concentration of resveratrol which is usually inactive (0.1µM or 100nM) appears to potently inhibit thrombin-induced platelet aggregation and increase antioxidant potential of the blood when in the presence of 0.5mM of D-glucaro-1,4-lactone, the active metabolite of Glucaric acid.[29]

Resveratrol and Calcium-D-Glucarate may also be synergistic at the level of suppressing DMBA-induced skin carcinogenesis.[30]

6.

Safety and Toxicity

6.1

General

In rats, 200mmol/kg of the diet potassium hydrogen glucarate for 3 generations has failed to confer toxic effects[31] and the dosage range of 70-350mmol/kg calcium-D-glucarate in the diet of both rats and mice used in previous studies does not appear to alter food intake or cause toxic effects.[32][33][34]

A phase I trial has been described (indirectly via an editorial[5]) noted that escalating doses of 1.5-9g of calcium-D-glucarate over 4 weeks was effective in inhibiting serum β-glucuronidase; no numbers were given, and the report cannot be located online.

Currently no known toxicity associated with high doses of Glucaric acid supplementation in research animals

References
1.^[No authors listedCalcium-D-glucarateAltern Med Rev.(2002 Aug)
3.^Dwivedi C, Heck WJ, Downie AA, Larroya S, Webb TEEffect of calcium glucarate on beta-glucuronidase activity and glucarate content of certain vegetables and fruitsBiochem Med Metab Biol.(1990 Apr)
4.^Walaszek Z, Szemraj J, Narog M, Adams AK, Kilgore J, Sherman U, Hanausek MMetabolism, uptake, and excretion of a D-glucaric acid salt and its potential use in cancer preventionCancer Detect Prev.(1997)
5.^Walaszek Z, Hanausek M, Narog M, Raich PC, Slaga TJMechanisms of lung cancer chemoprevention by D-glucarateChest.(2004 May)
6.^Walaszek Z, Hanausek-Walaszek M, Minton JP, Webb TEDietary glucarate as anti-promoter of 7,12-dimethylbenz{a}anthracene-induced mammary tumorigenesisCarcinogenesis.(1986 Sep)
8.^Heerdt AS, Young CW, Borgen PICalcium glucarate as a chemopreventive agent in breast cancerIsr J Med Sci.(1995 Feb-Mar)
13.^Nemoto N, Hirakawa T, Takayama SGlucuronidation of benzo{a}pyrene in hamster embryo cellsChem Biol Interact.(1978 Jul)
14.^Jørgensen A, Glessing AM, Rasmussen LJ, Andersen OBiotransformation of the polycyclic aromatic hydrocarbon pyrene in the marine polychaete Nereis virensEnviron Toxicol Chem.(2005 Nov)
17.^Poon R, Villeneuve DC, Chu I, Kinach RHPLC determination of D-glucaric acid in human urineJ Anal Toxicol.(1993 May-Jun)
18.^Pacifici GM, Gucci A, Giuliani LTestosterone sulphation and glucuronidation in the human liver: interindividual variabilityEur J Drug Metab Pharmacokinet.(1997 Jul-Sep)
19.^Ekström L, Cevenini L, Michelini E, Schulze J, Thörngren JO, Belanger A, Guillemette C, Garle M, Roda A, Rane ATestosterone challenge and androgen receptor activity in relation to UGT2B17 genotypesEur J Clin Invest.(2013 Mar)
21.^Walaszek Z, Hanausek M, Sherman U, Adams AKAntiproliferative effect of dietary glucarate on the Sprague-Dawley rat mammary glandCancer Lett.(1990 Jan)
23.^Kowalczyk MC, Spears E, Narog M, Zoltaszek R, Kowalczyk P, Hanausek M, Yoshimi N, Slaga TJ, Walaszek ZModulation of biomarkers related to tumor initiation and promotion in mouse skin by a natural β-glucuronidase inhibitor and its precursorsOncol Rep.(2011 Sep)
25.^Lajolo C, Sgambato A, Maiorano E, Lucchese A, Capodiferro S, Favia G, Giuliani MCalcium glucarate inhibits DMBA-induced oral carcinogenesis in the hamster: histomorphometric evaluationAnticancer Res.(2010 Mar)
26.^Yoshimi N, Walaszek Z, Mori H, Hanausek M, Szemraj J, Slaga TJInhibition of azoxymethane-induced rat colon carcinogenesis by potassium hydrogen D-glucarateInt J Oncol.(2000 Jan)
28.^Takada H, Hirooka T, Hiramatsu Y, Yamamoto MEffect of beta-glucuronidase inhibitor on azoxymethane-induced colonic carcinogenesis in ratsCancer Res.(1982 Jan)
29.^Olas B, Saluk-Juszczak J, Wachowicz BD-glucaro 1,4-lactone and resveratrol as antioxidants in blood plateletsCell Biol Toxicol.(2008 Apr)
30.^Kowalczyk MC, Kowalczyk P, Tolstykh O, Hanausek M, Walaszek Z, Slaga TJSynergistic effects of combined phytochemicals and skin cancer prevention in SENCAR miceCancer Prev Res (Phila).(2010 Feb)
33.^Walaszek Z, Hanausek-Walaszek M, Webb TEDietary glucarate-mediated reduction of sensitivity of murine strains to chemical carcinogenesisCancer Lett.(1986 Oct)