Indole Plus provides the clinically recommended level of stabilized indole-3-carbinol supported by a unique delivery system that promotes a favorable pH environment at the receptor sites for maximum uptake and utilization of I3C.
Indole Plus is manufactured in a state-fo-the-art, humidity and temperature controlled facility and is assayed for activity and potency no fewer than 4 times during the manufacturing process.
A plant based protein coating stabilizes the potency and activity of the I3C and protects it from the damaging effects of oxidation.
Ingredients per Tablet:
Indole 3-Carbinol 200 mg
L-Taurine (pharmaceutical grade amino acid) 20 mg
L-Glycine (pharmaceutical grade amino acid) 20 mg
Oxidase (5000 units/gram) 5 mg
Pyridoxal-5-phosphate 5 mg
Other Ingredients: Dicalcium phosphate, microcrystalline cellulose, silica and pharmaceutical glaze.
Two tablets in the A.M. on an empty stomach or near empty stomach.
In recent years there has been considerable interest in the effects of estrogen exposure on hormone related diseases including breast, uterine and prostate cancer (1-4). Excessive estrogen, whether endogenous (from within the body) or exogenous (originating outside the body), is being studied in both men and women. Optimizing estrogen metabolism with dietary changes, nutritional supplements and exercise, has proven to be extremely beneficial. Indole 3 Carbinol (I3C) has been investigated for its effects on estrogen metabolism as well as its chemopreventive and tumor suppressing properties (5, 6). Derived from plant sources, I3C is found in cruciferous vegetables such as broccoli, cabbage, cauliflower, Brussels sprouts and bokchoi.
Before we discuss the benefits of I3C, let's briefly review estrogen and its metabolites. Estrogen is a name used to describe the family of hormones consisting of Estrone (E1), Estradiol (E2) and Estriol (E3). Estrogens are converted from testosterone and androstenedione by way of the aromatase enzyme. Aromatase activity is present in many tissues including the liver, fat cells and skin. Estrogens are also synthesized in the ovaries. Estradiol, the most predominant estrogen hormone, is converted to estrone and finally to estriol. Estrogens are bound to a protein known as sex hormone binding globulin (SHBG). Binding the hormone to a protein (SHBG) supplies a circulating pool of the estrogens, which most likely provides a safeguard against sudden variations in the plasma level. Changes in SHBG due to normal aging or thyroid dysfunction can affect estrogen metabolism. (7)
Downstream metabolites of estrogen have been the principal focus of current hormone research. Estrogen is metabolized primarily in the liver using the Phase 1 hydroxylation enzymes and Phase II methylation, glucuronidation and sulfation pathways. The cytochrome P-450 enzymes are responsible for the hydroxylation of estradiol and estrone in the Phase I pathway. There are two crucial positions on the estrogen molecule where hydroxylation takes place, either at the 2 carbon (C-2) site or at the 16 carbon (C-16 ) position, yielding 2-hydroxyestrone (2-OH) and 16 - hydroxyestrone (16 -OH) respectively. Hydroxylation at the 4-carbon (C-4) position has a slight involvement, yielding 4-hydroxyestrone (4-OH). The C-2 metabolite, 2-OH, presents very weak estrogenic action and is often referred to as the good estrogen(8), while the 16 -OH and 4-OH metabolites have significant estrogenic activity implicating them as tumor promoting metabolites (9). There is a considerable body of evidence relating the 2-hydroxyestrone (2-OH) and 16 - hydroxyestrone (16 -OH) ratio to an increase risk of breast cancer (10). Women with elevated levels of 2-hydroxyestrone (2-OH) had a lower risk of breast cancer, while women with elevated 16 -hydroxyestrone showed increased risk (8).
Indole 3 Carbinol (I3C) and breast cancer
Estrogen, through its binding to the estrogen receptor (ER), plays an important role in breast cancer cell proliferation and tumor development (11). Various researchers suggest that Indole 3 Carbinol (I3C) exhibits potent antitumor activity by regulating estrogen activity and metabolism (11). One method of action for I3C is its ability to increase levels of 2-hydroxyestrone (2-OH), the so-called good estrogen, and decrease 4-hydroxyestrone (4-OH), and 16 -hydroxyestrone (16 - OH), potential carcinogenic estrogen metabolites (9, 12). Another probable scenario is that I3C and its metabolite diindolylmethane (DIM) inhibit estrogen-induced proliferation of MCF-7 human breast cancer cells (13). Further substantiation comes from Tiwari et al, who disclosed that I3C inhibits the growth of estrogen-responsive cell line MCF-7 while at the same time up regulates 2- hydroxyestrone (2-OH) (14). Meng et al found that I3C inhibits cell adhesion, up-regulates a tumor-suppressing gene, known as PTEN and limited metastasis (15). The protective effects of I3C on human breast cancer may also be due to its ability to induce cellular apoptosis (16). This course of action may be critical in limiting tumor growth.
Indole 3 Carbinol (I3C) and tamoxifen
The anti-estrogen drug tamoxifen is commonly used to treat breast cancer. Studies combining I3C with tamoxifen have demonstrated positive results. The combination works together to inhibit the growth of the estrogen-dependent human MCF-7 breast cancer cell line more effectively than either agent alone. (17, 18)
Post-menopausal Estrogen Replacement Therapy
There is still considerable controversy about the increased risk of breast cancer with postmenopausal estrogen administration. Serum levels of estradiol produced by commonly prescribed doses of postmenopausal estrogen therapy are equal to those of the follicular phase of the menstrual cycle. However, these levels may be near the threshold of breast cancer promoting effects when combined with genetics and lifestyle factors. According to Zumoff et al, the risk of breast cancer with postmenopausal estrogen replacement can be reduced by various methods, including the use of I3C (19). These researchers suggest that women on estrogen replacement therapy will have some protection against tumor development by decreasing 16 -hydroxyestrone (16 -OH) levels with I3C supplementation.
Endometrial and cervical tumors
Human papillomavirus (HPV) infects the genital tract and is generally acknowledged to be a contributing mediator of cervical cancer. However, HPV infection alone is not enough to bring on cervical cancer. Additional factors, such as hormones, are thought to contribute to the development and/or progression of this disease. 16 -hydroxyestrone (16 -OH) appears to be necessary for the development of abnormal cell growth as well as the death of healthy cells.(20) Oral supplementation of I3C has been found to reduce tumor development of the endometrium and cervix (20-22). The positive effects were due to the improvement in the 2/16 alphahydroxyestrone ratios.
Estrogens and men
Testosterone or dihydrotestosterone (DHT) in combination with estradiol seems to be implicated in the widespread and uncontrolled division of prostate cells that result in benign prostatic hypertrophy (BPH) (7). Correlations were found between prostate-specific antigen (PSA) levels, testosterone, epitestosterone and estradiol (3), while the estrogen metabolites have been associated with prostate tumor development (1, 2, 4). From their research, Chimni et al concluded that I3C inhibited the growth of prostate cancer cells. I3C appears to suppress tumorpromoting agents such as cyclin-dependent kinase 6 (CDK6) and Retinoblastoma (Rb) protein in prostate cells.
People all around the world are being exposed to a multitude of foreign chemicals known as xenobiotics (7). Xenobiotics (Xeno is from Greek meaning stranger) are any compounds foreign to the body. These compounds can be found in environmental pollutants, pesticides, drugs and food additives. As of 1996, more than 200,000 manufactured environmental chemicals exist. The liver is the primary organ involved in the detoxification and elimination of xenobiotics (7). Many of these foreign compounds exhibit hormone-like characteristics. Exposure to these exogenous estrogens may directly or indirectly modify estrogen metabolism (23). If they are not properly detoxified and eliminated, serious health problems may present themselves. Earlier research illustrates that some organochlorine-based pesticides raised the production of 16 alphahydroxyestrone relative to 2-hydroxyestrone in MCF-7 breast cancer cells (24, 25). As previously discussed, I3C has been shown to modify this ratio. Tobacco smoke also contains several exogenous carcinogens including nitrosamine 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Human and animal studies reveal that I3C may inhibit lung tumor formation by enhancing the liver clearance of NNK (26).
By measuring the urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alphahydroxyestrone, optimum dosing of I3C was determined. In a study by Wong et al, it was suggested that 300-400 mg of I3C daily was the minimum effective dose (27). In conclusion, I3C has many benefits, including the ability to modulate 2/16 alpha-hydroxyestrone ratios and provide antimutagenic and anticarcinogenic properties against a variety of carcinogens (28).