by Thomas Incledon, PhD(c), RD, LD/LN, RPT, NSCA-CPT, CSCS
Introduction
Scientists have known that higher intakes of cruciferous vegetables such as cabbage, broccoli, and cauliflower are associated with a lower incidence of a variety of cancers (1,2) and that certain compounds within these foods could decrease the effects of cancer- causing chemicals (3). One of these compounds is called glucobrassicin. After ingestion of glucobrassicin (from cruciferous vegetables), several compounds are formed in the gastrointestinal tract, including indole-3-carbinol or I3C (3). I3C can be converted into 3,3’-diindolyl methane (DIM). DIM can also be produced directly from glucobrassicin (3). The significance of these Trivial Pursuit-type details is that studies indicated that I3C or one of its metabolites (i.e. DIM) may act as a chemo-preventative agent. The logical recommendation would be to tell people to eat foods containing these agents on a consistent basis in order to maintain a reduced risk for breast and other types of cancers. This logical recommendation however, fails to address individual choices of the consumer, which are often influenced by a variety of factors, including food availability and food preferences. Additionally, the relative safety of food products makes studying their active components especially attractive given that the development of cancer fighting drugs can take 20-40 years to obtain approval for use. This article will discuss recent research on two compounds isolated from cruciferous vegetables and how they are being used as anti-cancer agents.
Estrogens: Both Friends and Foes
To make sense of how indole-3-carbinol (I3C) and/or diindolylmethane (DIM) affect us, we need to understand their role in estrogen metabolism. Estrogens are necessary for a number of important functions including bone maintenance and female sexual development. Estrogen metabolism involves the conversion of the potent estrogen estradiol into less potent estrogens. The figure below depicts the C2 (carbon 2) and C16 alpha hydroxylation of estradiol (the most potent estrogen in people). Hydroxylation is just a fancy way of describing the addition of an OH molecule to the given carbon number. Estradiol can be reversibly converted into estrone (a less potent estrogen). The liver can then metabolize estrone into 2-hydroxyestrone by hydroxylating the second carbon. This steroid can in turn be converted into 2-methoxyestrone. 2-hydroxyestrone and 2-methoxyestrone are termed catechol estrogens. They are weak estrogens 4 and in some cases act as antiestrogens (5,6). The pathway to the right side of the figure demonstrates that estrone can be hydroxylated at the 16th carbon position to form 16 alpha-hydroxyestrone. This steroid can in turn be converted into estriol. An increase in 16 alpha-hydroxyestrone production has been linked to an increase in breast cancer (7,8). After understanding the impact that influencing estrogen metabolism could have on breast cancer risk, researchers speculated that it would seem wise to reduce hydroxylation of the 16th carbon and increase hydroxylation of the 2nd carbon of estrone.
Human Studies
Numerous studies exist in the literature examining the effects of I3C on various cell and animal cancer models (see reviews by Kelloff 9-12). Collectively, these studies generally report beneficial effects. This early work stimulated interest in the National Cancer Institute to develop a plan for systematically studying the therapeutic potential of I3C as a chemopreventative agent (9,13). In an earlier human trial, three months of ingesting 400 mg of I3C per day resulted in an increased production of 2-hydroxyestrone (14), thus lending further support to the idea of using I3C in the prevention of breast cancer. Three years later a dose-ranging study was published (15). Doses of 0, 50, 100, 200, 300, and 400 mg of I3C were ingested each day by 57 women at risk for breast cancer. The minimum effective dose was determined to be 300 mg per day. Toxicity analysis indicated that there were no abnormalities in clinical chemistries or complete blood counts, except for two subjects that had unexplained small increases in a liver enzyme used to assess liver function. It should be pointed out that up to the time of writing this article, no studies have shown that I3C or any of its metabolites have actually prevented breast cancer in humans. As interesting as the data is thus far, there are still many questions that need to be answered.
In addition to breast cancer, I3C has been studied as a therapeutic agent for other clinical conditions. Recurrent respiratory papillomatosis (RRP) is a rare disease characterized by benign growths in the mucosa from the mouth to the lungs. The suspected etiologic agent of RRP has been human papilloma virus (HPV), types 6 and 11 (16). A case report of a 52-month old girl indicated that after initiating a protocol consisting of 190 mg of pure I3C and 2 oz of cabbage juice, she remained free of growths for the 45-month follow-up period (16). This isolated case report prompted further investigation by some of these researchers (17). In their next study, subjects included children and adults. Children were dosed based upon their body weight, while adults consumed 200 mg two times daily. Six out of 18 subjects had complete cessation of their papillomas, six others had reduced papilloma growth rates, and the remaining six experienced no effects of I3C treatment on the rate of papilloma growth (17). Laser surgery is the most widely practiced method of treatment for papilloma growth. Often times the papillomas grow back and patients often require multiple surgeries. The impressive findings from these preliminary reports warrant further investigation of I3C in the treatment of RRP. Interestingly, the clinical effectiveness of I3C in reducing the papilloma growths correlated with the changes in 2-hydroxyestrone and 16alpha-hydroxyestrone. It seems possible that HPV infection may impact estrogen metabolism.
Another potentially HPV-induced disease is cervical cancer. Precancerous lesions of the cervix can be treated with chemopreventative agents to prevent the development of cervical and vaginal cancer (18). In a placebo controlled trial in humans, 200 mg per day of I3C resulted in complete regression of cervical precancerous growth in four out of eight patients. 400 mg per day resulted in complete regression in four out of nine patients. In the placebo group, none of the patients had complete regression. By pooling the results from the animal and human studies, it seems that I3C has therapeutic potential against HPV-induced growths of the cervix, vagina, and respiratory tract. Caution should be practiced when taking I3C and anticipating a positive outcome (i.e. complete remission), as many of the subjects/patients in these studies experienced no effect from the treatment. This indicates a strong need for monitoring by a qualified healthcare professional during treatment with I3C, so that the effectiveness can be assessed.
The Claims Game
Numerous claims have been made for I3C and DIM. These range from cancer fighting properties to muscle building promises. are should be taken when trying to apply results from a study on one population (i.e. obese men and women) to other groups (i.e. non-obese, athletes). While increasing the ratio of 2 hydroxyestrone to 16 alpha-hydroxyestrone appears to be a sound strategy for reducing the risk for various cancers and cardiovascular disease, it may not work for everyone. Body composition strongly influences C2 hydroxylation of estrone in humans (19,20). The hydroxylation of the second carbon in lean people is very high. Increasing it further may be difficult to accomplish and may not provide any additional effects. A published study on male subjects taking ANDRO-6; which contained daily doses of 300 mg androstenedione, 150 mg DHEA, 750 mg Tribulus terrestris, 625 mg chrysin, 300 mg indole-3-carbinol, and 540 mg saw palmetto, found an increase in estradiol and estrone levels (21). Healthcare practitioners need to be careful of applying the data from obese subjects and cancer patients to healthier populations, as the results from one group may not apply to the other.
Future Research
Most of the research thus far has focused on I3C. It is known that I3C is actually a prodrug that is converted by stomach acid to DIM and indolylcarbazole (22,23). This is why I3C is effective only when given orally and does not exert an effect when injected (24). Since a 350-500 mg dose of I3C is roughly the equivalent of 300-500 mg of raw cabbage or Brussels sprouts, a comparison study of the relative effectiveness of whole foods vs. isolated agents would be useful for guiding healthcare recommendations. Future research should compare the effects of DIM against I3C, especially in populations where GI function may be compromised and thus minimal conversion of I3C to DIM would take place. Other areas that present exciting research opportunities are the combination of I3C or DIM along with other agents for treating breast cancer and cardiovascular disease. Cell studies indicate the combination of I3C and tamoxifen can arrest breast cancer cell growth (25). 2-hydroxyestrone reduces LDL oxidation (26-27) and 2-methoxyestrone inhibits smooth muscle cell proliferation (28). Future research examining the effects of I3C or DIM alone and in conjunction with Vitamin E and CoQ10 for the prevention of atherosclerosis would be very exciting.
In conclusion, most research thus far has focused on I3C. At doses of 200-400 mg per day, it appears to have therapeutic potential as a chemopreventative agent.
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