Phytonutrient Supplements For Cancer Prevention and Health Promotion

The supplemental use of certain phytonutrients from cruciferous vegetables has great potential for the prevention of human cancer. Specifically, the discovery that certain cruciferous indoles — diindolylmethane and indole-3-carbinol (I3C) — also promote the healthy metabolism of estrogen has greatly expanded their use as effective dietary supplements for estrogen-related conditions.

Besides possible cancer prevention, the uses for absorbable diindolylmethane have included benefits for perimenopausal women, in premenstrual syndrome (PMS), in endometriosis, and in cervical dysplasia. Women on estrogen replacement (HRT) also benefit from supplementation, as well as men with estrogen-related conditions, including prostate hypertrophy.

In choosing dietary supplements containing either diindolylmethane or I3C, it is important to understand their differences as phytonutrients, including their contrasting potential for interaction with other compounds. These differences have important long-term safety implications.

Introduction to cruciferous indole phytonutrients

Cruciferous vegetables (broccoli, cabbage, cauliflower, Brussels spouts, and bok choi) are in the news as powerful sources of cancer-preventive phytonutrition.

A recent study of Seattle men showed that three or more servings of cruciferous vegetables a week can reduce prostate cancer risk almost by half (1). For women however, the news is not so clear. In a large prospective study of 350,000 women, no protection from breast cancer could be attributed to dietary fruits and vegetables, or to the highest intake of cruciferous vegetables (2). Since other controlled studies in women have documented clear, beneficial action from cruciferous dietary supplements (3), there is a growing basis for adding cruciferous phytonutrients to the fruits and vegetables of a healthy diet.

The active and beneficial substances in cruciferous vegetables have been shown to be absorbable diindolylmethane and its precursor, indole-3-carbinol (I3C) (4). Supplemental use of these substances has a long history in cancer prevention research. With expanding applications in preventive nutrition, their use in women has actually been shown to reduce risk status for breast cancer (5) and cause the regression and disappearance of advanced cervical dysplasia (6). The supplemental use of diindolylmethane and I3C are under active investigation (7). These natural products are increasingly available as dietary supplements for healthier estrogen metabolism, peri-menopause, men�s health and the reduction of cancer risks.

Significant amounts of diindolylmethane are found in cruciferous plants following crushing (8). This contrasts with I3C which, due to its unstable nature, is only transiently present, primarily during digestion (9). I3C is the natural precursor to diindolylmethane, which is formed from a “condensation reaction” in which one I3C molecule combines with another. The resulting diindolylmethane is a “di-indole,” or double molecule, formed from two I3C molecules. Release of active diindolylmethane is facilitated by enzymes in the plant and is also due to the action of gastric acid on I3C released during digestion.

Pure forms of these natural substances derived from plant-based precursors are now available as dietary supplements. An informed choice between I3C or active diindolylmethane as a supplement requires an understanding of their relative merits and safety as phytonutrients. This review will compare and contrast important differences between diindolylmethane and I3C.

Diindolylmethane and I3C have different physical and phytochemical characteristics

Based on well-known physical characteristics, diindolylmethane is very stable in water and acid, but highly insoluble. I3C is soluble but highly reactive, resulting in over 20 condensation products (including diindolylmethane) when exposed to stomach acid (10). When I3C is kept dissolved in water, or buffered in weakly acidic solutions, a greater conversion to diindolylmethane occurs. In contrast, diindolylmethane requires a supplemental delivery system for improved solubility and complete gastrointestinal absorption.

I3C requires careful storage, avoiding heat, moisture and light to slow its rapid breakdown on the shelf. Taken as a dietary supplement, I3C requires gastric acid for conversion to active products. I3C is more irritating to the stomach than diindolylmethane, due to its chemical reactivity (11). I3C is also much more prone to interaction with components of food (especially vitamin C), which limits its conversion into diindolylmethane and other condensation products.

Conversion from I3C into diindolylmethane not only requires a precise acidity, it requires time. This conversion may proceed slowly, requiring more time than most foods typically spend in the intestinal tract.

A compelling study favoring the use of diindolylmethane over I3C demonstrated the fact that following an oral dose of I3C in humans, only diindolylmethane (and no I3C) was found circulating in the bloodstream of test subjects (12). This study used a highly sensitive detection method, thus confirming that I3C disappears after entry into our stomachs, with no direct benefits being attributable to absorbed I3C.

This study also documented that over 90% of an oral dose of I3C is converted into non-diindolylmethane “condensation products” of uncertain structure, uptake and activity.

Benefits for healthy estrogen metabolism

The history of supplemental use of phytonutrients from cruciferous vegetables began more than 20 years ago with research showing that either broccoli (13), pure diindolylmethane (14), or pure I3C (14) prevented chemically-induced breast cancer in animals.

In the 1990s, it was discovered that supplemental use of both diindolylmethane and I3C is associated with a beneficial shift in estrogen metabolism (15). Formulations of both diindolylmethane (16) and I3C (5), when used as dietary supplements, have been shown to reliably increase the 2-hydroxylation of estrogen, increasing the 2/16 ratio of estrogen metabolites. This ratio (also known as the “good-to-bad” balance of estrogen) (17) has now been shown to be a predictor of future breast cancer, based on a prospective study of 5,000 Italian women (18).

In this study, the future risk of developing breast cancer over a four-year period was reduced in the premenopausal women who demonstrated the highest 2/16 ratio. In a second study, a favorable ratio of higher 2/16 was also seen in benign conditions compared to breast cancer cases which had lower ratios (52).

A patented formulation of absorbable diindolylmethane (19) has been shown to result in a significant increase in the 2/16 ratio at one-tenth the dose of I3C. Women require supplemental I3C at 300 or 400 mg/day to significantly increase the ratio (5). Animal studies have clearly shown that it is diindolylmethane and not I3C that is the active promoter of greater 2-hydroxylation of estrogen associated with a cancer-resistant estrogen metabolism (20).

Besides being the active phytonutrient promoting beneficial estrogen metabolism, diindolylmethane now has been shown to actually treat breast cancer in animals (21). In this study, breast cancer was induced in animals with dimethylbenzanthracene (DMBA). Once tumors were present, diindolylmethane supplementation was begun. At the same dose now used in human studies, diindolylmethane completely stopped tumor growth.

When the same study was conducted with I3C (using a dose 50 times greater than current human use), no effect on tumor growth was observed (22). However, I3C, like diindolylmethane (14), has been shown to prevent the occurrence of breast cancer in animals. In separate studies, I3C was shown to prevent spontaneous (56) and induced (14, 57) breast cancer.

Apart from therapeutic potential, dietary supplement use of absorbable diindolylmethane and I3C relates to hormonal balance and symptoms of “estrogen dominance.” Supplemental use requires consideration of long-term safety. The reactivity, instability, and observed side effects from I3C raise questions and concerns about its safety in comparison to diindolylmethane.

The safety of absorbable diindolylmethane versus I3C

Diindolylmethane is less reactive and less of an enzyme inducer than I3C. This difference explains a number of the side effects seen with I3C. Doubling the typical dose of I3C from 400 to 800 mg/day causes dizziness, unsteady gait, and signs of nervous system toxicity in humans (23). Similar side effects were observed during I3C use in animals (24).

No side effects of any sort are seen when pure diindolylmethane is used even in huge doses in animals, or when the usual dose of 150 mg/day of absorbable, formulated diindolylmethane (containing 40 mg of diindolylmethane) is tripled to 450 mg/day in human subjects (25).

I3C has a number of safety concerns related to its long-term use as a dietary supplement. These safety concerns have to do with I3C’s action as a non-specific inducer of powerful cytochrome enzymes responsible for “Phase I” detoxification metabolism (26). Overactive Phase I metabolism may be a risk for activating potential carcinogens, especially in the colon (27). A study in rats has shown increased colon tumors in chemically treated rats given I3C as a dietary supplement (28).

Indolocarbazole (or ICZ) is one notable example of an unwanted byproduct that arises from exposing I3C to stomach acid (29). ICZ is produced from I3C during digestion and resembles dioxin in structure and enzyme-inducing activity. ICZ has been linked to oxidative DNA damage (30) and unwanted estrogen metabolites (31, 58).

With the more stable diindolylmethane, there is zero production of ICZ or other unwanted I3C reaction products. Diindolylmethane is able to promote beneficial estrogen metabolism and improve perimenopausal symptoms at a lower dose than I3C, without the creation of byproducts of uncertain safety.

Since diindolylmethane does not induce the wide array of enzymes that I3C does, there is less of a chance of interaction with other nutrients, hormones or medications. With I3C, antacids and heartburn medications will tend to change an individual�s response due to I3C�s dependence on stomach pH for activation.

Regarding its safe use in young women, diindolylmethane has been initially tested during combined use with oral contraceptives. Based on its lack of enzyme induction or inhibition, no problem interactions were seen (32).

I3C has not been tested with oral contraceptives, but its powerful enzyme-inducing activities have great potential to alter the metabolism of both oral contraceptives, certain herbs, various prescription drugs, and hormones other than estrogen. In side-by-side tests of I3C and diindolylmethane, I3C has proven to be the most enzyme inductive (34, 53, 54). Diindolylmethane is clearly a more precise modulator of enzyme activity than I3C.

Maintaining healthy testosterone in perimenopause, PMS, and male aging

The different enzyme-inducing activities of diindolylmethane and I3C impact their ability to maintain a healthy testosterone balance in both women and men. In animals, I3C has been shown to promote more rapid metabolism and inactivation of testosterone (33). A recent comparison of I3C and absorbable diindolylmethane in an independently conducted safety test in animals (34) showed that at typical human doses, only I3C promoted increased liver enzyme activity responsible for testosterone metabolism (35).

At higher doses, dramatic increases in these and other undesirable enzyme activities were seen with I3C, but not with diindolylmethane. I3C typically interacted with enzyme subtypes and other substances, including: CYP2B1 (testosterone metabolism), CYP3A4 (oral contraceptives, testosterone, natural substances, drugs), CYP2C9 (anti-seizure medications), CYP2D6 (prescription drugs) and CYP2E1 (prescription drugs).

As an inducer of CYP3A4 enzymes, I3C acts in an analogous fashion to hypericin from extracts of St. John�s Wort (Hypericum perforatum) (36). St. John�s Wort preparations have been shown to accelerate the metabolism and clearance of anti-viral drugs used in HIV infection, the transplant immune-suppressant, cyclosporine, and the heart phytomedicine, digoxin (37). I3C may possess similar undesirable ‘flushing’ activities but has not been tested clinically.

Perimenopause is a time in women�s lives characterized by higher-than-normal estrogen production and lower progesterone production, especially during the second half or “luteal” phase of the menstrual cycle (38). In women suffering from PMS (premenstrual syndrome), severity of symptoms is associated with the degree of estrogen elevation in affected women (39).

Also notable in perimenopausal women is a deficiency of “free” or unbound testosterone during the middle of the menstrual cycle (40). Testosterone deficiency is associated with depressed mood, loss of libido, and weight gain. Testosterone replacement can resolve these symptoms in perimenopausal women, thus confirming the importance of maintaining a proper testosterone balance in middle-aged women.

Since levels of free testosterone in women are 25 times lower than in men, even small changes in testosterone levels and protein binding can produce symptoms. As a supplement which helps support testosterone and progesterone levels, diindolylmethane is the preferred cruciferous indole for perimenopausal nutritional support.

As a more efficient promoter of beneficial 2-hydroxy estrogen metabolism than I3C, diindolylmethane can more predictably and safely increase 2-hydroxy estrogen metabolites. These unique estrogen metabolites stimulate progesterone production (55) and compete with testosterone for protein binding. This helps to maintain testosterone in its active, free form that has been shown to support healthy mood and libido in women with PMS (41).

Cruciferous supplements for men

The same dynamics for maintaining higher total and free testosterone levels apply to healthy aging in men. Estrogen metabolism slows as men age, especially when coupled with obesity and regular alcohol use. Avoiding overactive testosterone metabolism, and reducing the conversion of testosterone into estrogen are goals of nutritional support in middle-aged and older men.

It is well documented that estrogen accumulates in the prostate gland starting at about age 50 (42) and that estrogen is associated with the degree of prostate enlargement (43). Based on animal and human testing, diindolylmethane is again preferable to I3C in the setting of men�s health. Men using diindolylmethane can minimize or avoid accelerating their testosterone metabolism, especially the unwanted conversion of testosterone into estrogen.

In a safety study of the two phytonutrients (11), only I3C increased the activity of “aromatase” (CYP19), the enzyme responsible for converting testosterone into estrogen. In contrast, supplementation with absorbable diindolylmethane resulted in reports of improved prostate function based on reduced nighttime urination in symptomatic older men.

Use of Diindolylmethane more closely resembles the human diet

Once absorbed, diindolylmethane is uniquely active in promoting healthy estrogen metabolism and improving symptoms of estrogen-related imbalance in both men and women.

However, the absorption of crystalline diindolylmethane is very limited, due to its extreme lack of solubility. In early testing, human volunteers took 300 mg of crystalline diindolylmethane for one week without a change in before and after measurements of urinary estrogen 2/16 metabolites. Subsequently, taking one-tenth of this amount of diindolylmethane in an absorbable formulation (30 mg of diindolylmethane provided in 100 mg of formulation) significantly increased the levels of beneficial 2-hydroxy estrogen metabolites in urine. (30 mg of diindolylmethane is about twice the amount of diindolylmethane obtainable from large daily portions of cruciferous vegetables.)

This advantage for absorbable diindolylmethane (16) allows an intake that is only 3-4 times more than the amount of diindolylmethane available from cruciferous vegetables alone. The use of this patented formulation effectively provides an absorbable amount of diindolylmethane equal to or greater than the amount found in two pounds of raw cabbage.

When I3C is used as a supplement, no more than 10% is converted to diindolylmethane, even under optimum pH conditions in the upper intestine (duodenum). Thus, a minimum of 300�400 mg/day of I3C is needed to dependably improve the 2/16 estrogen ratio (5), which equates to 30-40 mg/day of absorbable diindolylmethane. However, this dosage of 300�400 mg/day for I3C puts the supplement dose at 30-40 times the possible dietary exposure, with a corresponding increase in non-diindolylmethane I3C condensation products that are highly enzyme inducing.

Compatibility with other hormone balancing substances: Soy, Red Clover, Black Cohosh and Chasteberry Extract

Soy, Red Clover, Black Cohosh, and Chasteberry are sources of phytonutrients utilized for their hormone modulating qualities. As seen with the interaction described for I3C and St. John�s Wort, the actions of CYP3A and CYP2B cytochrome enzymes are often involved in the metabolism of active phytochemicals (36). The greater enzyme inducing effects of I3C create a risk for overactive metabolism and elimination of desirable phytoestrogens. Ideally, there should be no concerns in taking these substances in conjunction with cruciferous phytonutrients.

While both diindolylmethane and a triple molecule derived from I3C called the “Cyclic Trimer” have been noted to have estrogenic qualities (44, 45), these actions have not been observed during human use. In fact, neither diindolylmethane, I3C, nor the phytoestrogens listed above can substitute for the desirable activities of natural estrogen and estrogen�s beneficial metabolites.

Regarding the potential of soy phytoestrogens for breast cancer prevention, a recent large study from Japan revealed no benefit, even after years of soy intake with more isoflavones than with regular use of isoflavone concentrates (46). Though supplementation with approximately 200 mg/day of soy isoflavones has been shown to modestly increase the production of beneficial estrogen metabolites (47), this is much less of an effect than is seen with absorbable diindolylmethane or I3C.

Of greater concern is the stimulation of breast cancer cell growth seen with phytoestrogens (48). Most important are the observations made on humans taking soy supplements. Normal women kept on a soy-supplemented diet showed significant hyper-proliferation of breast epithelial cells (49). Unlike diindolylmethane and I3C, soy isoflavones do not inhibit chemically induced breast cancer in animals (50).

While phytoestrogens like the isoflavones found in soy, red clover and black cohosh can be used in conjunction with diindolylmethane, they do not offer the same beneficial modulation of estrogen action seen with diindolylmethane. As competitors to estrogen, phytoestrogens may interfere with normal estrogenic support for successful brain aging. Recent reports suggest that soy phytoestrogen intake may be associated with accelerated brain aging and cognitive decline in both women and men (51).

Unlike soy isoflavones, which can make breast symptoms worse, absorbable diindolylmethane has been associated with improvement in premenstrual breast pain and the resolution of breast cysts. In addition, supplementation with absorbable diindolylmethane is also associated with improved symptoms of PMS, improved cervical health as documented by normalized Pap Smears, and reduced menstrual pain.

In addition, increased weight loss has been noted in both women and men on lower carbohydrate diets, when supplemented with higher doses of absorbable diindolylmethane. None of these benefits have been observed with soy supplementation alone.

Summary and Conclusion

There are important phytonutrient differences between diindolylmethane and I3C. As a dietary supplement, absorbable diindolylmethane provides an active and documented entity from cruciferous vegetables at levels only 3 times greater than the amount available from large portions of raw vegetables.

In contrast, I3C requires a dose 30 times greater of a more reactive and unpredictable phytochemical. The many byproducts resulting from the digestion of I3C may contribute to benefits, but may also create safety risks.

The following table summarizes the risk and benefit profiles of absorbable diindolylmethane and I3C. Practitioners and patients should take note of the differences as they turn to cruciferous phytonutrients for hormonal balance, healthy aging, and cancer prevention.

Correspondence to:
Michael A. Zeligs, M.D.
BioResponse, LLC

P.O. Box 288
Boulder, Colorado 80306 U.S.A.
E-mail: zeligsmd@bio-response.com
Order DIM: www.hormonalbalance.com