Calcium D glucarate

Calcium-D-glucarate also known as calcium glucarate, glucarate, calcium saccharate or calcium-D-saccharate, is the calcium salt of D-glucaric acid, a substance produced naturally in small amounts by mammals, including humans ¹. Calcium-D-glucarate is also found in many fruits and vegetables with the highest concentrations to be found in oranges, apples, grapefruit, carrots, potatoes, lettuce, bean sprouts and cruciferous vegetables (e.g., arugula, cauliflower, cabbage, kale, garden cress, bok choy, broccoli, Brussels sprouts, and similar green leaf vegetables) ². Oral supplementation of calcium-D-glucarate has been shown to inhibit beta-glucuronidase, an enzyme produced by colonic microflora and involved in Phase II liver detoxification. Elevated beta-glucuronidase activity is associated with an increased risk for various cancers, particularly hormone-dependent cancers such as breast, prostate, and colon cancers ³. Other potential clinical applications of oral calcium-D-glucarate include regulation of estrogen metabolism and as a lipid-lowering agent.

Calcium-D-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-D-glucarate had a slower onset of tumor development and a smaller number of tumors than rats that were not fed calcium glucarate. Calcium-D-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-D-glucarate has these effects in humans.

Upon ingestion and exposure to the acidic environment of the stomach, calcium-D-glucarate is metabolized to form D-glucaric acid. D-glucaric acid is further metabolized in the gastrointestinal tract into three compounds existing in equilibrium and comprised of approximately 40-percent D-glucaric acid, 30-percent D-glucaro-1,4-lactone, and 30-percent D-glucaro-6,3-lactone ¹. These compounds are then transported to the blood and various internal organs and are subsequently excreted in the urine and bile. Although D-glucaro-1,4-lactone seems to be the most pharmacologically active of the three, it is not commercially available. Also, calcium-D-glucarate administration results in longer inhibition of beta-glucuronidase (five hours versus one hour) than does D-glucaro-1,4-lactone, so it is the compound used ⁴.

D-glucaro-1,4-lactone increases detoxification of carcinogens and tumor promoters by inhibiting beta-glucuronidase and preventing the hydrolysis of their glucuronides. D-glucaro-1,4-lactone was found to be formed from supplemented calcium-D-glucarate salt in the stomach and it is absorbed from the intestinal track, transported with the blood to different internal organs, and excreted in urine and, to a lesser extent, in bile ³. D-glucaro-1,4-lactone and its precursors exert their anticancer action in part through alterations in steroidogenesis accompanied by changes in the hormonal environment and proliferative status of the target organs. D-glucarates not only suppress cell proliferation and inflammation, but also induce apoptosis. By supplementing D-glucarates, one can favor the body’s natural defense mechanism for eliminating carcinogens and tumor promoters and their effects.

In a preliminary human study, calcium-D-glucarate supplementation suppressed beta-glucuronidase levels while increasing serum glucaric acid levels ⁵.

Calcium-D-glucarate is not an essential nutrient so, technically, no deficiency state exists ¹. However, since it is only produced in small amounts by humans, it is important that dietary intake be adequate. Diets low in fruits (particularly oranges, apples, and grapefruit) and cruciferous vegetables (broccoli, cabbage, and brussel sprouts) may result in a relative deficiency of calcium-D-glucarate and its metabolites. Research has shown a low level of D-glucaric acid correlates with a higher level of beta-glucuronidase, which in turn is associated with an increased risk for various cancers ⁶.

Calcium-D-glucarate mechanism of action

Calcium-D-glucarate’s detoxifying and anticarcinogenic properties are attributed to its ability to increase glucuronidation and excretion of potentially toxic compounds ¹. It is the glucarate component, not the calcium, accounts for the activity of calcium-D-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 ⁶. During Phase II detoxification, chemical carcinogens, steroid hormones, and other lipid-soluble toxins are conjugated with glucuronic acid in the liver (glucuronidation) and excreted through the biliary tract. Beta-glucuronidase is capable of deconjugating these potential toxins, making it possible for them to be reabsorbed rather than excreted. Beta-glucuronidase has been shown to decrease the rate of elimination of estrogen and carcinogens such as polycyclic aromatic hydrocarbons and nitrosamines by deconjugation ⁷. Inhibition of beta-glucuronidase activity with calcium-D-glucarate improves excretion of metabolized estrogen and carcinogens ⁸. Calcium-D-glucarate can also be metabolized by gut bacteria, inhibit bacterial beta-glucuronidase and potentially alter the enterohepatic cycle.

D-glucaro-1,4-lactone is the metabolite that has been shown to inhibit beta-glucuronidase activity, increasing excretion of conjugated xenobiotic compounds and decreasing activity of harmful substances that are most active in their deconjugated state ⁹. Inhibition of beta-glucuronidase ultimately results in potentially decreasing the risk of the formation of a cancer (carcinogenesis or tumorigenesis) ¹⁰. In addition, by reducing the beta-glucuronidase viability and activity of intestinal bacteria, salts of D-glucaric acid have been shown to enhance enterohepatic circulation and reduce steady state levels of cholesterol synthesis, resulting in decreased serum lipid levels ¹¹.

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 ¹². Antitumorigenic effects of topical calcium glucarate may be due to stimulated differentiation via induction of transglutaminase activity and suppression of proliferation ¹³, as well as inhibition of thymidine kinase and aryl hydrocarbon hydroxylase activities, thus preventing carcinogen-DNA binding ¹⁴. 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 ¹⁵. 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 ¹⁶. 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 ¹⁷.

Calcium-D-glucarate benefits

Cancer prevention and treatment

Although lab studies suggest anticancer effects, calcium-D-glucarate or calcium glucarate has not been shown to treat or prevent cancer in humans. A handful of animal studies show that calcium-D-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-D-glucarate supplementation might reduce cancer risk for some individuals. More well-designed studies are needed to confirm such effects.

The anticarcinogenic properties of D-glucaric acid and its salts have been studied in various animal tumor models, including colon ¹⁸, prostate ⁶, lung ¹⁹, liver ²⁰, skin ²¹ and breast cancer ⁷, with the mechanism of action for tumor inhibition being very similar in each. These studies demonstrated decreases in beta-glucuronidase activity, carcinogen levels and tumorigenesis.

In colon ²² and lung cancer models ¹², calcium glucarate administration exerted chemopreventive effects in the post-initiation phase of carcinogenesis. Dietary calcium-D-glucarate also inhibited oral carcinogenesis ²³. Topical calcium glucarate suppressed tumor development in murine skin tumors ²⁴ and enhanced chemopreventive effects were achieved with a topical butyric acid, nicotinamide, and calcium glucarate combination ¹⁵. A combination of topical ursolic acid and dietary calcium glucarate supplementation reduced skin tumor promotion and inflammatory signaling ¹⁷.

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-D-glucarate supplementation might reduce the cancer risk of some individuals ⁵. Subsequent studies have not materialized and are needed to confirm such effects.

Breast cancer

A number of studies have shown calcium-D-glucarate alone and in combination with retinoids, inhibits mammary carcinogenesis in rats by as much as 70 percent ⁴. Natural retinoids have been shown to be effective chemopreventive agents at high doses, but unfortunately the cumulative toxic effects of high doses have restricted their prolonged use. Several studies have demonstrated low-dose retinoids in combination with calcium glucarate interact synergistically to inhibit mammary tumor growth in both animal models and human cell lines ²⁵. The mechanisms responsible for the chemopreventive effects of these two agents may be similar. Both retinoids and calcium-D-glucarate inhibit carcinogenesis during the promotion and initiation phases. Calcium-D-glucarate inhibits protein tyrosine kinase-C activity and induces transformation growth factor beta, possibly resulting in an increase in cellular differentiation and slower progression through the cell cycle ²⁶. Retinoids induce many of these same biochemical effects ²⁷. Additionally, calcium-D-glucarate enhances glucuronidation and subsequent excretion of carcinogens and other cancer-promoting agents. However, published human studies on calcium-D-glucarate and breast cancer are few. Patients with breast cancer sometimes self-medicate with calcium-D-glucarate supplements following surgery or adjunctive treatments. The glucarate component, not the calcium, is thought to account for its activity. Following calcium-D-glucarate administration, glucarate is converted to D-glucaro-1,4-lactone, which inhibits beta-glucuronidase ⁶.

Test tube and animal studies suggest that inhibition of beta-glucuronidase may prevent carcinogenesis ²⁸, as well as initiation and promotion of cancer cells ¹³. Increased elimination of carcinogens and hormones, including estrogen, has also been shown ⁸.

Colon cancer

Studies in rats have shown D-glucarate salts to inhibit colon carcinogenesis alone and in combination with 5-fluorouracil (5-FU). In one study, calcium-D-glucarate markedly inhibited azoxymethane-induced colon carcinogenesis as evidenced by a 60-percent reduction in both tumor incidence and multiplicity. It was hypothesized that malignant cell proliferation was suppressed by inhibition of beta-glucuronidase. Another possible mechanism may involve alterations in cholesterol synthesis or its conversion to bile acids ¹⁸. The second study demonstrated that salts of D-glucarate, in combination with 5-fluorouracil (5-FU) in rat colon tumor explants, resulted in a potentiation of 5-FU’s antitumor activity. D-glucarate alone also showed antitumor activity ²⁹.

Liver cancer

Hepatocarcinogenesis is thought to be preceded by premalignant hepatic foci that are subsequently transformed to malignant cells. Two separate rat studies by a group of researchers at Ohio State University have demonstrated calcium-D-glucarate delays the appearance of altered hepatic foci and significantly inhibits hepatocarcinogenesis, if given during both the initiation and promotion phases. Maximal inhibition was obtained when calcium-D-glucarate was administered by gavage prior to the carcinogenic agent, diethyl nitrosamine ³⁰.

Lung cancer

A study conducted on mice demonstrated calcium-D-glucarate inhibits benzo[a]pyrene’s ability to bind DNA and induce pulmonary adenomas ¹⁹. Another unpublished phase I clinical trial of 62 patients found D-glucaric acid levels were approximately 29-percent lower in smokers than non-smokers. Regardless of gender, K-ras (anoncogene linked to lung cancer) mutations were found to be present in 38 percent of subjects who smoked, while no K-ras mutations were found in the non-smoking control subjects. It was hypothesized that D-glucaric acid deficiency correlates with K-ras mutations and might be indicative of a higher risk for developing lung cancer ³¹.

Skin cancer

The efficacy of dietary calcium-D-glucarate as a chemopreventative agent has also been studied in the mouse skin tumorigenesis system. Mice were given 7,12-dimethylbenz[a]anthracene (DMBA) to induce skin tumorigenesis and were fed either a regular chow diet or a chow diet fortified with calcium-D-glucarate. When fed the calcium-D-glucarate chow through both the initiation and promotion phases, papilloma formation was inhibited by over 30 percent. The data indicate that supplementation of calcium-D-glucarate results in a marked alteration in the retention, activity, and metabolism of carcinogenic substances ³².

Calcium-D-glucarate estrogen metabolism

Calcium-D-glucarate’s inhibition of beta-glucuronidase activity allows the body to excretehormones such as estrogen before they can be-come reabsorbed. Oral administration of largedoses of calcium-D-glucarate have been shown tolower serum estrogen levels in rats by 23 percent.21Because many breast cancers are estrogen-depen-dent, calcium-D-glucarate’s ability to affect estro-gen and other hormone levels has led to Phase Iclinical trials at several major cancer centers inthe United States. Results of these studies are pending.

Calcium-D-glucarate lipid lowering

Side effects of currently available hypolipidemic agents present a need for safe and effective lipid-lowering agents. Calcium-D-glucarate have been shown to significantly reduce total serum cholesterol in rats by as much as 12-15 percent and LDL-cholesterol (“bad” cholesterol) by 30-35 percent. Preliminary results in humans show calcium-D-glucarate reduced total serum cholesterol up to 12 percent, LDL-cholesterol up to 28 percent and triglycerides up to 43 percent. The lipid-lowering effect of calcium-D-glucarate may be attributed to improved enterohepatic circulation, resulting in increased excretion of bile acids and a reduction in steady state levels of cholesterol biosynthesis ³³.

Calcium-D-glucarate dosage

The recommended oral dosage of calcium-D-glucarate is generally in the range of 1500-3000 mg daily. Until human trials have been completed the optimal dosage remains elusive.

Calcium-D-glucarate side effects

Preliminary results of clinical trials in humans have shown calcium-D-glucarate is without side effects ⁵. No adverse effects have been observed after prolonged feeding to rats or mice at concentrations of 70, 140 or even 350 mmol/kg ³⁴.

Drug interactions

There are no known drug interactions with calcium-D-glucarate, but many drugs and hormones are metabolized in the liver via glucuronidation. Therefore, taking calcium-D-glucarate may increase elimination of these substances, possibly reducing their effectiveness.

References

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