Calcium Glucarate

• How It Works

  Although lab studies suggest anticancer effects, calcium glucarate has not been shown to treat or prevent cancer in humans.

  Calcium glucarate is absorbed in the intestine and converted into a molecule that inhibits beta-glucuronidase, to possibly increase elimination of toxic substances. For example, rats that were exposed to carcinogens and fed calcium glucarate had a slower onset of tumor development and a smaller number of tumors than rats that were not fed calcium glucarate. Calcium glucarate also increases estrogen elimination, which may reduce estrogen levels in the body. This explains its use as supportive care among estrogen-sensitive breast cancer patients. However, positive results in animal studies do not always mean a similar approach will work in humans. In addition, no clinical trials have tested whether calcium glucarate has these effects in humans.

• Purported Uses
  • To detoxify the body
    Laboratory and animal studies suggest that calcium glucarate speeds up the elimination of carcinogens from the body. Human studies have not been conducted.
  • To prevent and treat cancer
    A handful of animal studies show that calcium glucarate can slow the development and reduce the number of tumors in rats exposed to carcinogens, but human data are lacking. Only one small study in humans suggests that calcium glucarate supplementation might reduce cancer risk for some individuals. More well-designed studies are needed to confirm such effects.
• Scientific Name

  D-Glucaric acid salt

• Clinical Summary

  Calcium glucarate is the salt and the commercial form of glucaric acid, which occurs naturally in a variety of foods including apples, oranges, broccoli, and spinach ⁽¹⁾. Calcium glucarate and other derivatives have been used to prevent and treat cancer. Patients with breast cancer sometimes self-medicate with calcium glucarate supplements following surgery or adjunctive treatments. The glucarate component, not the calcium, is thought to account for its activity. Following administration, glucarate is converted to D-glucaro-1,4-lactone, which inhibits beta-glucuronidase ⁽⁴⁾.

  In vitro and animal studies suggest that inhibition of beta-glucuronidase may prevent carcinogenesis ⁽⁵⁾, as well as initiation and promotion of cancer cells ^(3) (6). Increased elimination of carcinogens and hormones, including estrogen, has also been shown ⁽²⁾. In colon ⁽⁷⁾ and lung ⁽⁸⁾ cancer models, calcium glucarate administration exerted chemopreventive effects in the post-initiation phase of carcinogenesis. Dietary calcium glucarate also inhibited oral carcinogenesis ⁽⁹⁾. Topical calcium glucarate suppressed tumor development in murine skin tumors ^{(6) (10) (11)}, and enhanced chemopreventive effects were achieved with a topical butyric acid, nicotinamide, and calcium glucarate combination ^(12) (13). A combination of topical ursolic acid and dietary calcium glucarate supplementation reduced skin tumor promotion and inflammatory signaling ⁽¹⁴⁾.

  Preliminary findings from a human study suggest that low glucaric acid levels and/or high beta-glucuronidase levels are markers of detoxification system impairment, and that calcium glucarate supplementation might reduce the cancer risk of some individuals ⁽¹⁵⁾. Subsequent studies have not materialized and are needed to confirm such effects.

• Food Sources

  Cruciferous vegetables such as broccoli, cabbage, and Brussels sprouts; oranges, grapefruit, apples, spinach, carrots, potatoes, lettuce, bean sprouts, grapes ^{(1) (4) (16)}

• Purported Uses
  • Cancer prevention
  • Cancer treatment
  • Detoxification
• Mechanism of Action

  The glucarate component, not the calcium, accounts for the activity of calcium glucarate, which is absorbed from the gut as D-glucaric acid. This is further converted to D-glucaro-1,4-lactone, which is thought to inhibit beta-glucuronidase activity ⁽⁴⁾. Beta-glucuronidase has been shown to decrease the rate of elimination of estrogen and carcinogens such as polycyclic aromatic hydrocarbons and nitrosamines by deconjugation ⁽³⁾. Inhibition of beta-glucuronidase activity with calcium glucarate improves excretion of metabolized estrogen and carcinogens ⁽²⁾. D-glucarate can also be metabolized by gut bacteria, inhibit bacterial beta-glucuronidase, and potentially alter the enterohepatic cycle.

  In animal studies, calcium glucarate reduced the quantity of benzo[a]pyrene-induced lung lesions with mutated K-ras and p53 genes in the post-initiation phase via DNA adduct removal, mutagenic suppression, and anti-inflammatory activity ⁽⁸⁾. Antitumorigenic effects of topical calcium glucarate may be due to stimulated differentiation via induction of transglutaminase activity and suppression of proliferation ⁽⁶⁾, as well as inhibition of thymidine kinase and aryl hydrocarbon hydroxylase activities, thus preventing carcinogen-DNA binding ⁽¹⁰⁾. Enhanced chemopreventive effects by a topical butyric acid, nicotinamide, and calcium glucarate combination used on murine skin tumors occurred via induced mitochondria-mediated apoptosis, upregulated p21, and downregulated Bcl-2, mut p53 ⁽¹²⁾. In another study this combination regulated miR-203 status through epigenetic or biogenetic modulations before and after tumor development to a greater degree than each of the individual compounds ⁽¹³⁾. Reduced epidermal hyperplasia with a combination of topical ursolic acid and dietary calcium glucarate supplementation caused a marked decrease in COX-2 and IL-6 expression ⁽¹⁴⁾.

  In a preliminary human study, calcium glucarate supplementation suppressed beta-glucuronidase levels while increasing serum glucaric acid levels ⁽¹⁵⁾.

• Adverse Reactions

  In a preliminary study, calcium glucarate was well-tolerated with no toxicity reported ⁽¹⁵⁾.

• References

  1. Dwivedi C, et al. Effect of calcium glucarate on b-glucuronidase activity and glucarate content of certain vegetables and fruits. Biochem Med Metab Bio 1990;43:83-92.

  2. Heerdt AS, et al. Calcium glucarate as a chemopreventive agent in breast cancer. Isr J Med Sci 1995;31:101-5.

  3. Abou-issa H, et al. Relative efficacy of glucarate on the initiation and promotion phases of rat mammary carcinogenesis. Anticancer Res 1995;15:805-10.

  4. Walaszek Z, et al. Metabolism, uptake, and excretion of a d-glucaric acid salt and its potential use in cancer prevention. Cancer Detect Prevent 1997;21:178-90.

  5. Yoshimi N, et al. Inhibition of azoxymethane-induced rat colon carcinogenesis by potassium hydrogen D-glucarate. Int J Oncol 2000;16:43-8.

  6. Singh J, Gupta KP. Calcium glucarate prevents tumor formation in mouse skin. Biomed Environ Sci 2003 Mar;16(1):9-16.

  7. Wargovich MJ, Jimenez A, McKee K, et al. Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression. Carcinogenesis. Jun 2000;21(6):1149-1155.

  8. Hanausek M, Walaszek Z, Szemraj J, et al. Modulation of biomarkers during chemoprevention of mouse lung tumorigenesis by D-glucarate. Chest. May 2004;125(5 Suppl):149s.

  9. Lajolo C, Sgambato A, Maiorano E, et al. Calcium glucarate inhibits DMBA-induced oral carcinogenesis in the hamster: histomorphometric evaluation. Anticancer Res. Mar 2010;30(3):843-849.

  10. Gupta KP, Singh J. Modulation of carcinogen metabolism and DNA interaction by calcium glucarate in mouse skin. Toxicol Sci. May 2004;79(1):47-55.

  11. Singh J, Gupta KP. Induction of apoptosis by calcium D-glucarate in 7,12-dimethyl benz [a] anthracene-exposed mouse skin. J Environ Pathol Toxicol Oncol. 2007;26(1):63-73.

  12. Tiwari P, Sahay S, Pandey M, et al. Combinatorial chemopreventive effect of butyric acid, nicotinamide and calcium glucarate against the 7,12-dimethylbenz(a)anthracene induced mouse skin tumorigenesis attained by enhancing the induction of intrinsic apoptotic events. Chem Biol Interact. Jan 25 2015;226:1-11.

  13. Tiwari P, Gupta KP. Modulation of miR-203 and its regulators as a function of time during the development of 7, 12 dimethylbenz [a] anthracene induced mouse skin tumors in presence or absence of the antitumor agents. Toxicol Appl Pharmacol. Jul 15 2014;278(2):148-158.

  14. Kowalczyk MC, Junco JJ, Kowalczyk P, et al. Effects of combined phytochemicals on skin tumorigenesis in SENCAR mice. Int J Oncol. Sep 2013;43(3):911-918.

  15. Walaszek Z, Hanausek M, Narog M, et al. Mechanisms of lung cancer chemoprevention by D-glucarate. Chest. May 2004;125(5 Suppl):149s-150s.

  16. Monograph. Calcium-D-glucarate. Altern Med Rev. Aug 2002;7(4):336-339.