Two cruciferous indoles -- Diindolylmethane (DIM) and its
precursor, Indole-3-carbinol (I3C) -- are increasingly popular
as dietary supplements. Researchers have been studying the role
of these substances in promoting healthier estrogen metabolism
and for potential use in estrogen-related conditions, including
cancer. Regarding women's health, use of cruciferous vegetable
indoles has importance for breast cancer prevention and for the
control of cervical dysplasia. Both DIM and I3C show real promise
in these areas, yet studies have also uncovered sharp contrasts
between them in one critical area -- consumer safety.
Anyone advocating the benefits of I3C over DIM is ignoring
the published scientific facts. A careful review of the research
reveals serious questions concerning the safety of I3C. For example,
the National Institute of Health (NIH) in its Chemoprevention
Branch Report on I3C safety issues says: "Subchronic, preclinical
toxicology studies in dogs have identified significant toxicities
associated with oral administration of I3C... The possible enhancing
effects of I3C on chemical carcinogenesis and toxicity should
be investigated, especially in light of the wide variety of enzymes
induced... The fact that the I3C condensation product ICZ has
both antiestrogenic and estrogenic activities also may have safety
implications... Additional genetic toxicity testing may be required."
This statement and the published evidence are clear -- I3C,
and in particular its reaction product ICZ, are associated with
a number of unwanted activities that are not compatible with
safe, long-term use. Misinformation raised about DIM and the
purported superiority of I3C are simply not supported by the
the Facts Straight on Cruciferous Supplements
First, there are many published
studies on DIM. There are over 40 studies in the National Library
of Medicine Database which involve DIM. In 2001 alone, seven
studies were published. In addition, well-controlled, independently-performed
human studies have been completed and are awaiting publication.
These include use of DIM showing statistically significant benefits
for recurrent breast pain and improvement of cervical dysplasia.
Second, ICZ (indolocarbazole) is not a safe derivative of
I3C. ICZ activates the dioxin receptor just like dioxin. ICZ
does not block it. It is DIM that blocks this receptor (2). This
is one of the key benefits of using a stable DIM supplement.
Third, more is not necessarily better. Having a family of
reactive products being generated does not provide broader cancer
protection if many of these products also have unwanted side
effects. Side effects are tolerable in certain cancer treatment
drugs for established cancer but not in nutritional substances
meant to prevent cancer in healthy individuals.
Fourth, DIM is not estrogenic or a growth promoter of cancer
cells when studied in intact humans or animals. When tested in
analogous experiments, I3C failed to prevent the progression
of cancer (6, 7).
As a physician and a researcher, I have worked with scientific
experts around the world to study the chemistry of I3C and to
identify its safest and most beneficial form. This led to the
identification of DIM as the safest, most active and most beneficial
I3C-related substance found in cruciferous vegetables, and to
the development of an effective, highly-absorbable DIM supplement.
DIM has been tested in humans. The entire basis of absorbable
DIM's introduction as a supplement was based on testing which
supported its safe and efficacious use. Many of these studies
involve side-by-side testing of DIM and I3C.
In year-long animal tests, independent university-based scientists
found evidence of I3C's lack of safety that justified concern
-- I3C was found to be highly enzyme-inducing, but DIM was not.
In a second test performed by an independent government laboratory,
confirming results again showed unwanted enzyme induction by
I3C but not DIM.
Ongoing placebo-controlled human testing is being performed
to confirm benefits for DIM observed in cervical dysplasia (40)
and breast cancer risk reduction (42). In fact, Leon Bradlow,
Ph.D., the original discoverer of the importance of cruciferous
indoles for breast health, now supports and advocates absorbable
DIM, and not I3C, as the preferred supplement. Dr. Bradlow actually
initiated and performed the majority of human and animal testing
Recent publications have begun to focus on DIM, recognizing
it as more advantageous than I3C. DIM has been shown to be more
potent and active than I3C in experimental cervical cancer (3).
When inducing cell death (apoptosis) in cervical cancer cells,
Dr. Karen Auborn, a renown cancer research scientist, states
that "DIM is a more effective inducer of apoptosis than
I3C" (3). Other work showed that DIM had a strong anti-proliferative
effect in human endometrial cancer cells (4). Indolocarbazole
(ICZ), the dioxin-like and enzyme-inducing reaction product arising
from I3C, notably failed to control the growth of these endometrial
cancer cells (4).
Unwanted enzyme-inducing effects
from I3C have also been shown in recent animal studies (5). This
work clearly demonstrates that oral I3C can increase production
of dangerous estrogen metabolites at the same time it increases
the beneficial 2-hydroxy metabolites. In effect, this cancels
out benefits for estrogen metabolism. Consistent with this, I3C
has been shown to be ineffective in controlling the growth of
experimental breast cancer (6, 7), while DIM succeeds (8, 9).
Let us now turn to the scientific basis for the NIH's concerns
about I3C safety. This involves a discussion of unwanted activity
associated with some of the many I3C reaction products (other
than DIM) which arise during I3C use.
the Scientific Facts into Perspective
Both I3C and DIM have been studied since the 1970s in experimental
models of cancer prevention. The majority of subsequent studies
involved I3C, not because it was better, but because it was available
and plentiful. I3C, however, is a highly reactive "pro-nutrient"
which undergoes complicated reactions once in water or stomach
I3C itself has been shown to not leave the stomach or circulate
in the blood since it is so reactive (11). Instead, a mixture
of I3C byproducts leaves the stomach, some being absorbed, but
most remaining in the intestinal tract. These I3C byproducts
are not the wholesome, well-studied, cancer preventive substances
that some wish they were. In truth, I3C has a mixed reputation
-- preventing cancer in some experiments but promoting cancer
in others (12,13).
Briefly, the reaction products from I3C can be described as
Indolocarbazole (ICZ) - ICZ resembles dioxin
in structure and function (14). Also, like dioxin, ICZ is a powerful
inhibitor of estrogen action. Though toxic in many other ways,
dioxin has been shown to prevent and treat breast cancer in animals.
ICZ is being explored as a possibly less toxic form of dioxin
to treat breast cancer. But like dioxin, ICZ does not block the
dioxin receptor. It activates it as aggressively as dioxin does
Though a down-regulator of the estrogen receptor system, ICZ
is itself estrogenic and is responsible for promoting enzymes
which produce 4-hydroxy estrogen, a metabolite associated with
uterine tumors (16) Though more quickly metabolized, ICZ shares
many of dioxin's toxicities. Like dioxin, ICZ has been shown
to be damaging to the thymus gland and immune system (17), and
to damage DNA (18).
Importantly, the reaction products arising from I3C have been
shown to negatively impact the immune system, resulting in lower
natural killer cell activity in animals (19). Like dioxin, I3C
and its reaction products have also been associated with reproductive
toxicity in animals (20, 25). Unlike I3C, DIM cannot be converted
into ICZ in vivo.
Ascorbigen (ASG) - ASG is the most plentifully
produced reaction product from I3C, arising from the combination
of I3C with vitamin C. ASG occurs following consumption of cruciferous
vegetables which contain abundant viatamin C. ASG arises from
I3C supplements only when the I3C is taken along with other supplements
or foods rich in Vitamin C.
Once produced in the stomach, a portion of ASG is then converted
into ICZ in the lower intestine (21). This makes ASG a source
for much of the unwanted enzyme promotion attributed to ICZ.
This was demonstrated when ASG was fed as a pure compound to
animals and measurements of estrogen metabolism showed increased
production of unwanted 4-hydroxy estrogen (22).
4-hydroxy estrogen is a carcinogenic estrogen metabolite,
increased after activation of the dioxin receptor. While some
preliminary work demonstrates anti-cancer activity by ASG in
animals, further testing reveals that ASG's natural breakdown
results in the release of formaldehyde (23). This makes ASG a
highly undesirable I3C product during human use. Other undesirable
reactions involving ASG have been described resulting in the
formation of DNA damaging mutagens (24).
Linear Trimer (LTR) - LTR is an anti-estrogen,
but clearly another activator of the dioxin receptor. This was
recently proven by feeding I3C to pregnant rats and studying
the livers of the mothers and their offspring (25). LTR was found
in both mother and offspring. Most importantly, the induction
of the enzyme source for 4-hydroxy estrogen, CYP 1B1, was also
found together with measurable LTR in the rat pup livers. This
is evidence that LTR crosses the placenta and activates the dioxin
receptor in an analogous way to ICZ in both mother and developing
Cyclic Trimer (CTR) - CTR is produced in stomach
acid by the condensation of three I3C molecules into a ring structure.
CTR is a direct acting estrogenic compound, occupying and activating
the estrogen receptor. CTR powerfully stimulates the growth of
growth of breast cancer cells, in the presence or absence of
Indole-3-acetonitrile (IAN) also arises from I3C in
the acidic milieu of the stomach. Though shown to be protective
in an animal model of stomach cancer, IAN has also been shown
to be mutagenic (47) and give rise to DNA-damaging reaction products
(27). This occurs when I3C is ingested in the presence of nitrates
commonly present in foods (47).
More importantly, IAN is disruptive of cell membranes, activating
the arachadonic fatty acid cascade leading to the production
of LTB4, a reactive leukotrine (28). Leukotrines are closely
related to Lipoxins, which like ICZ, may contribute to further
activation of the of the dioxin receptor (29).
There are multiple, additional reaction products
from I3C which occur but have been poorly studied. Most of these
also resemble ICZ in their activity as activators of the dioxin
receptor. Since they are poorly absorbed, this action is especially
important for the cells lining the intestines and colon. It is
because of this action that I3C is associated with the enhancement
of colon cancer in animals (30) and damage to human colon cells
in culture (31).
Conditions have also been studied in animals in which cancer
promotion due to I3C was seen in other organ systems (32). With
higher pH as seen in the upper intestine and in the stomach with
the use of antacid medications like Cimetidine and Zantac, I3C
has recently been shown to form a separate, additional set of
reaction products (33). In these mild pH environments, I3C results
in toxic 3-methylindole leading to DNA-damaging complexes, called
Culture Studies can be Misleading
Much has been made of a cell culture study using DIM which
showed that in artificial estrogen-free conditions, DIM contributed
to the growth of breast cancer cells (34). This activity, observed
only in the complete absence of estrogen, is never seen in living
animals where estrogen is always present. In the presence of
estrogen, DIM is consistently anti-proliferative and reduces
the growth signal provided by estrogen (35). This includes growth-inhibiting
activity in both estrogen receptor positive and negative cancer
cell types (36). The estrogen-independent activation pathway
described by Riby et al (34) involves the increased phosphorylation
of estrogen receptor proteins, and not the direct interaction
of DIM with the estrogen receptor. This action may actually be
of benefit in cancer control.
Understood in context, this receptor activation pathway contributes
to the control of abnormal cell growth in living animals through
enhanced "programmed-cell-death" (apoptosis) and a
reduced tendency for the metastatic spread of cancer (37).
Unlike ICZ, LTR, CTR or ASG, DIM exerts its control over cancer
cell growth without activating the dioxin receptor or inducing
unwanted enzymes (38). Direct control over cancer cell growth
by DIM has now been shown in breast, uterine, cervical, ovarian,
and colon cancer cells. I3C has been noted to control cancer
cell growth in these cell types as well. However, in cell culture
media at 37 degrees Centigrade, most of the I3C is converted
to DIM in 24 hours (39). Since no ICZ and the other condensation
products formed in gastric acid occur in cell culture media,
DIM may very well be responsible for much of the activity attributed
to I3C in prior cell culture studies.
and Human Studies
Apart from the cell culture data, in vivo use in animal models
and clinical use in humans carries the most importance in deciding
safety and efficacy. DIM is the only cruciferous indole which
treats established breast cancer in animals. This has been shown
in separate studies by different investigators (8, 9). Giving
I3C as the supplement failed to control breast cancer growth
in an equivalent study (6).
Regarding human studies, DIM has demonstrated every benefit
known to accrue to I3C use. This includes shifting estrogen metabolism
to produce more protective 2-hydroxy metabolites. DIM also has
shown the same benefit as I3C in helping to resolve cervical
dysplasia. These studies will soon be presented and published
by the American Association of Cancer Research (40).
Plus, higher doses of DIM are
well-tolerated, unlike I3C, where higher doses produce side effects
such as dizziness and unsteady gait (41). Higher doses of absorbable
DIM are being used in monitored studies of cervical dysplasia,
in combined use with Tamoxifen, and in adults and children with
viral papillomas. This monitored use of high dose absorbable
DIM involves before and after testing of liver function in human
subjects and has revealed no abnormalities.
This demonstrated lack of side effects from high doses of
absorbable DIM further underscores its safety when used at lower
doses as a dietary supplement.
Currently, formal placebo-controlled studies using absorbable
DIM are in progress for cervical dysplasia and recurrent breast
pain in women. Open label studies without placebo are being conducted
for cervical dysplasia, cutaneous and plantar warts, and laryngeal
These human studies, often at ten times the typical supplement
dose of DIM which benefits estrogen metabolism, have reported
no side effects. More detailed human studies involving DIM are
planned to further examine its safe use in humans. This includes
a study approved at UC Berkeley in women with breast cancer where
absorbable DIM will be given to improve estrogen metabolism and
lower cancer risk status (42).
In contrast to this, a small trial of I3C in humans demonstrated
nausea and vomiting in 25 % of subjects when the typical dietary
supplement dose of 400 mg/day was tripled to 1200 mg (43).
about the Vitamin-E TPGS in the patented DIM formulation?
In absorbable DIM, pure (but poorly soluble) DIM is complexed
with Vitamin-E TPGS to provide for and enhance DIM's absorption.
Vitamin-E TPGS (Tocophersolan) is a well-known ingredient in
foods and pharmaceuticals. It is so safe as to appear on the
Generally Regarded As Safe (GRAS) list maintained for ingredients
by the FDA. Rarely are dietary supplement ingredients safe enough
to appear on this list. Proof of its safety has been established
in extensive testing, including testing by the NIH (44). Vitamin-E
TPGS is also used to improve the absorption of Vitamin-D (45)
and Vitamin-E (46) in infants.
is Effective and Safer than I3C
Use of absorbable DIM has been shown effective in amounts
close to that obtainable from our diet (0.3 mg/kg/day of DIM)
(40). I3C requires about 15 times more than this (4.5 mg/kg/day
(48)), and is associated with side effects (41, 43). In preventive
nutrition, even small risks and potential toxicities must be
taken seriously, lest the negatives outweigh the positives and
The I3C safety issues described
here should not be lightly dismissed -- every one of these safety
concerns must be addressed by anyone advocating I3C. Animal and
human testing raises the concern of I3C toxicity. Excessive enzyme
induction, as seen with I3C, is associated with disease promotion.
In contrast, DIM has a consistently positive safety record
which makes a strong argument for its safe, effective and long-term
use in humans. For those interested in a scientifically-based,
cruciferous supplement for estrogen-related concerns, DIM provides
distinct advantages over I3C. DIM is a conservative, well-studied,
safe, and clearly effective natural substance.
Copyright 2002 by Michel A. Zeligs,
All Rights Reserved
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