The
Cruciferous Choice: Diindolylmethane or I3C?
Phytonutrient
Supplements For
Cancer Prevention and Health Promotion
by
Michael A. Zeligs, M.D.
Abstract
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.
Copyright
2001 by Michael A. Zeligs, M.D., all rights reserved
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