What Every Woman Needs To Know About Indoles

Ever wonder why leafy green vegetables, like kale and spinach, are so good for you but you struggle to eat them?

After ready this article, you will want to get as much of this into you as possible!

Scientists have isolated indole-3-carbinol (I3C) as the active ingredient in cruciferous vegetables such as broccoli, cabbage, brussel sprouts, and cauliflower.

Experts have known for a long time that cruciferous vegetables are rich in cancer-fighting antioxidants. 

But, most people don’t eat enough to truly make a difference. And the amount of I3C varies with each crop harvested.

Combine that with the aging population’s digestive tract problems and we have what amounts to not enough I3C available from our diet to help our bodies fight disease.  

I3C + Estrogen

Estrogens are hormones necessary for various functions including bone maintenance and female sexual development.

However, we know that women with higher circulating estrogen levels have an increased breast-cancer risk. 

Estradiol and estrone interconvert; that is, they can easily change back and forth.

The body has to get rid of excess estrogen and has a sophisticated detoxification system to do so.

For example, the liver can then metabolize estrone and estradiol into 2-hydroxyestrone and 2-hydroxyestradiol by hydroxylating the second carbon.

These steroid daughter compounds can in turn be converted into 2-methoxy-estrone and 2-methoxyestrodial, which are called catechol estrogens.

These weak estrogens can act as anti-estrogens—that is, they can decrease other estrogen activity in the body. 

Based on estrogen metabolism’s influence on breast-cancer risk, researchers speculate that reducing hydroxylation of estrone’s 16th carbon and increasing hydroxylation of the second carbon would be a wise, protective measure.

I3C initiates a series of reactions in the body that culminates in the elimination of estrogen.

The process begins when I3C is ingested. Stomach acid converts it into a variety of products that ultimately induce the enzyme cytochrome P450, which signals the body to metabolize estrogen via the 2-hydroxylation pathway. By funneling estrogen into this “tumor suppressor” pathway.

I3C essentially “vacuums” away the estrogen.

Indole-3-Carbinol stimulates the rate at which the body expels estrogen through 2-hydroxylation.

A group of researchers investigated the effects on humans of short-term oral exposure to I3C, administering 400mg of I3C daily to test subjects for one week.

After I3C was consumed, the extent of 2-hydroxylation jumped from 29.3% to 45.6%.

In another study, 12 healthy volunteers ingested 6 – 7 mg of I3C per kg of body weight, per day over one-week.

After exposure to I3C, the rate of 2-hydroxylation in the subjects increased by 50%.

As I3C works to sweep the estrogen away from the tumor enhancer to the tumor suppressor pathway, it acts as an effective weapon against breast, cervical and skin cancer and respiratory papillomas.

Indoles + Estrogen: a study

Indole-3-carbinol is a negative regulator of estrogen. Studies increasingly indicate that dietary indole-3-carbinol (I3C) prevents the development of estrogen-enhanced cancers including breast, endometrial, and cervical cancers.

Epidemiological, laboratory, animal and translational studies support the efficacy of I3C. Whereas estrogen increases the growth and survival of tumors, I3C causes growth arrest and increased apoptosis and ameliorates the effects of estrogen.

Our long-range goal is to best use I3C together with other nutrients to achieve maximum benefits for cancer prevention.

This study examines the possibility that induction of growth arrest in response to DNA damage (GADD) in genes by diindolylmethane (DIM), which is the acid-catalyzed condensation product of I3C, promotes metabolically stressed cancer cells to undergo apoptosis.

We evaluated whether genistein, which is the major isoflavonoid in soy, would alter the ability of I3C/DIM to cause apoptosis and decrease expression driven by the estrogen receptor (ER)-alpha. Expression of GADD was evaluated by real-time reverse transcription-polymerase chain reaction.

Proliferation and apoptosis were measured by a mitochondrial function assay and by fluorescence-activated cell sorting analysis.

The luciferase reporter assay was used to specifically evaluate expression driven by ER-alpha.

The estrogen-sensitive MCF-7 breast cancer cell line was used for these studies.

We show a synergistic effect of I3C and genistein for induction of GADD expression, thus increasing apoptosis, and for decrease of expression driven by ER-alpha.

Because of the synergistic effect of I3C and genistein, the potential exists for prophylactic or therapeutic efficiency of lower concentrations of each phytochemical when used in combination.

Auborn KJ, Fan S, Rosen EM, Goodwin L, Chandraskaren A, Williams DE, Chen D, Carter TH. North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030, USA.

I3C + Breast Cancer

Researchers have examined the effects of I3C on cell and animal cancer models. Collectively, the results are generally positive.

This preliminary work stimulated interest at the National Cancer Institute in Bethesda, Md., which developed a plan to systematically study I3C’s therapeutic potential as a chemo-preventive agent.

In a randomized human trial at the Institute for Hormone Research in New York City, 60 female patients took 400 mg/day I3C for three months.

The regimen increased production of 2-hydroxyestrone, thus further supporting the theory that I3C may function as a preventive agent against breast cancer. 

Three years later, researchers at Strang Cancer Prevention Center in New York City studied 57 women at risk for breast cancer in a double-blind, placebo-controlled dose-ranging study using 0, 50, 100, 200, 300, and 400 mg I3C/day.1

The minimum effective dose to increase the ratio of 2-hydroxyestrone to 16-alpha-hydroxyestrone was 300 mg/day.

Toxicity analysis indicated no abnormalities in clinical chemistries or complete blood counts, except for two subjects who experienced unexplained slight, nonsignificant increases in a liver enzyme used to assess liver function. The dosage level was not stated. 

I3C + Cervical Dysplasia 

Women who get bad news from a Pap smear result may soon have a different treatment option.

New evidence suggests that indole-3-carbinol (I3C), a chemical found in broccoli family vegetables, may be able to reverse cervical dysplasia.

Cervical dysplasia is a pre-cancerous condition. Standard treatment involves watchful waiting, and, if it doesn’t go away by itself, invasive procedures such as freezing the surface of the cervix.

I3C may soon become a milder treatment alternative. 

A 12-week placebo-controlled trial of 30 women with stage II or III cervical dysplasia found that treatment with I3C at a dose of 200 or 400 mg daily significantly improved the rate at which the cervix spontaneously returned to normal.1

I3C appears to work in several ways, including partially inactivating estrogen, as well as fighting free radicals and directly interfering with tumor cell reproduction.7

I3C + Ovarian Cancer

Indole-3-carbinol (I3C) can completely destroy several different lines of ovarian cancer cells, according to a recent report to the Society of Gynecologic Oncologists.

A 12-week placebo-controlled trial of 30 women with stage II or III cervical dysplasia found that treatment with I3C at a dose of 200 or 400 mg daily significantly improved the rate at which the cervix spontaneously returned to normal.1 

In the placebo-controlled human trial, 200 mg/day I3C resulted in complete regression of cervical precancerous growth in four of eight patients, and 400 mg/day resulted in complete regression in four of nine patients. In the placebo group, no patients had complete regression. 

SOURCE: Long Island University Hospital study, presented as a paper to the Society of Gynecologic Oncologists, March, 2001.

I3C + Prostate Cancer

Prostate Cancer in North America equals that of Breast Cancer in women in that every year there are 200,000 new cases diagnosed with 40,000 deaths each year.

A study in the Journal of the National Cancer Institute shows that three or more servings of cruciferous vegetables a week slashes prostate cancer risk almost in half.

The study, which involved more than 600 men with prostate cancer, was conducted in the Seattle area.

This confirms data from a Canadian study showing that cruciferous vegetables, tomatoes, green vegetables and beans/lentils/nuts all substantially reduce the risk of prostate cancer. 

It’s presently unknown whether I3C is the only reason cruciferous vegetables protect against prostate cancer.

I3C is also potentially important in restoring communication between testosterone, estrogen and progesterone.

This can be critical because these hormones have a direct effect on the growth of prostate cancer cells.

One of I3C’s most important actions is to interfere with cancer cells’ ability to grow.

A normal cell goes through “checkpoints” to ensure that everything is okay before it replicates.

Cancer cells override the checkpoints, and grow at break neck speed. I3C restores the brakes.

By forcing the cancer cells to stop at the checkpoint, the body has an opportunity to destroy deviant cells and stop the growth of cancer.

Other Benefits

Besides altering estrogen metabolic pathways, I3C guards against the carcinogenic effects of two amines (IQ and PhIP) formed during the cooking process of proteinaceous foods.

These amines are carcinogenic in several strains of rats, inducing mammary and liver tumors in the animals.

Once activated by enzymes, PhIp and IQ yield cancer-causing DNA adducts. Indole-3-Carbinol inhibits this adduct formation by as much as 89%.

A summary of recent studies then shows that indoles increase the conversion of estradiol to “weaker” (2OHE) estrogen, which has been shown to reduce breast cancer incidence

  • Works in estrogen receptor negative breast cancer cells.
  • Stops human cancer cells from growing (54-61%) and provokes the cells to self-destruct (ap o ptosis).
  • Inhibits MCF7 human breast cancer cells better than tamoxifen under laboratory conditions.
  • Protects against the environmental toxin, dioxin.
  • Restores p21 tumor suppressor gene. 
  • Provides antioxidant protection.
  • doses of 200-400 mg per day, may have therapeutic potential as a chemopreventive agent. 

The difference between I3C and the other broccoli extract called diindolylmethane (DIM)?

Indole-3-carbinol (I3C) is a secondary metabolite found in cruciferous vegetables such as broccoli, cauliflower, kale, cabbage and brussel sprouts.

A secondary metabolite is one not found preformed in vegetables, but formed after an enzyme in the vegetable (myrosinase) is exposed to a phytochemcial in the vegetable (glucobrassicin).

This can occur only when vegetable cells are crushed or eaten, and is referred to as enzymatic hydrolysis. 

I3C, thus formed, is then broken down in the presence of acid (as in the acid environment of the stomach) to various by-products such as diindolylmethane (DIM), which are then absorbed.

I3C converts to DIM in the body. 

This is important because I3C has been shown to inhibit cancer cells in animal cancer models of the mammary, liver, and lung.

It is currently being evaluated in human clinical trials as a potential chemopreventive agent against breast and ovarian cancers. 

I3C appears to work by upregulating or modulating certain enzymes that improve the detoxification of various potential carcinogens—although it appears to be the breakdown products that have this effect rather than IC3 itself.

Furthermore, it is not clear that DIM is the only breakdown product of importance.9

Certainly DIM by itself has an effect, but these other products may also be important for the overall cancer-inhibiting action.

As most of the research to date has focused on I3C, it seems prudent at this time to use supplements containing I3C instead of DIM.

Just make sure you take it with meals and have sufficient acidifying capacity in your stomach.

Dan Lukaczer, N.D., is director of clinical research at the Functional Medicine Research Center, a division of Metagenics Inc., in Gig Harbor, Wash.

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