Calcium-D-glucarate - Monograph

Alternative Medicine Review, August, 2002

Introduction

Calcium-D-glucarate is the calcium salt of D-glucaric acid, a substance produced naturally in small amounts by mammals, including humans. Glucaric acid is also found in many fruits and vegetables with the highest concentrations to be found in oranges, apples, grapefruit, and cruciferous vegetables. (1) 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 wire an increased risk for various cancers, particularly hormone-dependent cancers such as breast, prostate, and colon cancers. (2) Other potential clinical applications of oral calcium-D-glucarate include regulation of estrogen metabolism and as a lipid-lowering agent.

Pharmacokinetics

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. 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. (3)

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. 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. 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. (4,5) Inhibition of beta-glucuronidase ultimately results in potentially decreasing the risk of carcinogenesis. (6) 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. (7)

Deficiency States

Calcium-D-glucarate is not an essential nutrient so, technically, no deficiency state exists. 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. (2)

Clinical Indications

Cancer

The anticarcinogenic properties of D-glucaric acid and its salts have been studied in various animal tumor models, including colon, (8,9) prostate, (2) lung, (10) liver, (11,12) skin, (13) and breast (14-18) cancer, 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. The preponderance of research, however, has been conducted on mammary tumors in the rat, the animal model most frequently used for breast cancer research.

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. (3) 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. (14-18) 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. (15) Retinoids induce many of these same biochemical effects. (19) Additionally, calcium-D-glucarate enhances glucuronidation and subsequent excretion of carcinogens and other cancer-promoting agents.