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Improve the quality of your life. 11/28/2006 All About Indole-3-C Carbinol and Cancer Protection   How Cruciferous Vegetables and their I3C Content Help Reduce Cancer Risk -------------------------------------------------------------------------------- by James Meschino,DC,MS There is a growing awareness among health practitioners and the general public about the importance of nutrition and antioxidants, flavonoids, soy isoflavones and dietary fiber. One of the less appreciated bioactive agents strongly associated with reducing risk of many common cancers is indole-3-carbinol (I3C), found exclusively in cruciferous vegetables (broccoli, cauliflower, cabbage, Brussels sprouts, kale and bok choy), and in various supplements. This important biological agent is known to speed up the detoxification of many potentially harmful chemicals (including carcinogens); provide antioxidant support; block the overproduction of certain hormones that are linked to increased risk of breast and prostate cancer; and act as a phytoestrogen (plant-based estrogen) that can bind to estrogen receptors on reproductive tissue and exert anti-cancer influences. I3C has been shown to be one of the major anti-cancer substances found in cruciferous vegetables. Frequent consumption of cruciferous vegetables is associated with reduced risk of cancer in many human epidemiological studies and in animal experiments.1-8 I3C is a member of the class of sulfurous chemicals called glucosinolates (previously called thioglucosides).9 It is formed from parent compounds whenever cruciferous vegetables are crushed or cooked.10,11 I3C and other glucosinolates (e.g., other indoles and isothiocyanates, such as sulforphane) are antioxidants and potent stimulators of phase I and II detoxification enzymes in the liver and intestinal epithelial cells.12-14 Detoxification Support The liver and epithelial cells of the intestinal tract contain the major detoxification centers in of the body, referred to as phase I and II detoxification. Almost two quarts of blood pass through the liver every minute of our lives. Among other functions, liver cells are capable of detoxifying a large number of end-products of metabolism, drugs, xenbiotics, hormones and other compounds, including certain carcinogens. Phase I and II detoxification is known to be a vital aspect of preventing the accumulation of toxins in the body, and neutralizing and eliminating various cancer-causing agents and procarcinogens. Phase I detoxification enzymes can directly neutralize some dangerous chemicals, but primarily convert most compounds into intermediate end-products that must be further acted upon by the phase II enzyme system. Many of the intermediates formed by phase I detoxification are more dangerous to the body than were the original compounds. Many of these intermediates are free radicals that are known to cause DNA mutations and other damage, and can deplete the liver of its glutathione stores if sufficient nutritional support for glutathione synthesis is not available. The phase II detoxification enzymes primarily act to conjugate intermediate end-products (formed in phase I detoxification) with various amino acids and other chemicals that neutralize these intermediates and make them easier for the body to eliminate (e.g., attaching sulfur via sulfation makes many compounds more water-soluble and easier to eliminate in the urine). I3C is one of the very few exogenous agents that can speed phase I and II detoxification centers in the liver and the intestinal epithelial cells, and can improve the function of phase II glutathione-S-transferase detoxification activity, an extremely important pathway in the elimination of many dangerous chemicals. Many researchers indicate that the ability of cruciferous vegetables to stimulate Phase I and II detoxification, especially their I3C content, is a primary factor in which these nutrients are related to reduced cancer risk in humans. Animal studies have repeatedly shown that when animals are exposed to or injected with carcinogens, the animals receiving the cruciferous vegetables or the I3C in their food have a significantly lower tumor yield and incidence than those fed the same diet, but without cruciferous vegetables or I3C fortification.15-17 Phytoestrogen Support I3C is a phytoestrogen (plant-based estrogen), and can bind to estrogen receptors in the body, reducing the ability of stronger estrogens from overstimulating reproductive tissues such as the breast; cervix; uterus; and in males, the prostate gland. Researchers have recently discovered that breast cells, for instance, contain alpha and beta estrogen receptors. The body's estrogens (estradiol, estrone and estriol); estrogen replacement therapy; and the estrogen in oral contraceptives primarily stimulate the alpha-receptors, which encourage breast cells (and estrogen-dependent breast cancer cells), to rapidly divide and proliferate. As breast cells divide more rapidly, they are more inclined to make genetic mistakes and create cancerous mutations. This is how high exposure to estrogen, hormone replacement therapy and oral contraceptives are linked to the increased risk of breast cancer. Conversely, phytoestrogens are known to primarily stimulate the beta receptors on breast cells, which encourages a slower, more controlled cell division rate associated with reducing the risk of breast cancer. Further, phytoestrogens also bind to alpha receptors, but have only .0001 to .00001 the estrogen effect of estradiol, and thus compete for binding on these receptors with other more powerful estrogens. In this way, phytoestrogens are also capable of toning down the estrogenic influence of more powerful estrogens on various reproductive tissues. This effect also helps to prevent hyperproliferation of breast cells. Epidemiological studies consistently show that a higher ingestion of I3C foods is highly associated with the prevention of reproductive organ cancers in women and men.3,4,8 I3C promotes the metabolism of certain endogenous estrogens (estrone) into a safer, less cancer-promoting form (2-OH-estrone), further helping to reduce risk of reproductive organ cancers (according to modern wisdom). Some women naturally convert more of their estrone hormone to 16-hydroxyestrone (H), considered by some researchers a biomarker for increased risk of breast cancer. Supplementation with I3C has been shown to alter genetic expression in such a way as to encourage greater activity of the enzyme that converts estrone into 2-H, which is considered to be protective against breast cancer. Thus, all women may benefit in this regard as the intake of I3C helps to improve the 2-hydroxy-to-16-H ratio. This may be important in men, as well, from the standpoint of preventing prostate cancer.18-20 Human studies have used a dose of 300-400 mg per day to demonstrate a significant change in the 2-hydroxy-to-16-H ratio, but a lower dosage may still be effective.33 Prevention of Female Reproductive Cancers In experimental animal testing with mice and rats, I3C and Brussels sprouts each have demonstrated an ability to reduce mammary cancer incidence in animals exposed to carcinogens known to promote mammary cancer in these species.21-22 As mentioned earlier in human studies, the ingestion of I3C has been shown to increase the metabolism of estrone hormone to 2-H, rather than the 16-alpha-H metabolite. Studies indicate that 16-alpha-H is associated with an increased risk of breast cancer in humans and conversely, 2-H is associated with a reduction in breast cancer risk. Thus, I3C influences the body's enzyme systems in a fashion that favorably influences the 2-H-to-16-alpha-H ratio, helping to reduce risk of breast cancer.20,21,23,24 A large prospective study involving 5,000 Italian women, and a second study of patients with either benign or malignant breast lesions, highlighted the ability of a higher two-to-16-H ratio to predict which women were less prone to breast cancer development.33 Breast Cancer Epidemiological studies and experimental evidence strongly suggests that I3C may reduce breast cancer risk through the above-cited mechanisms.25-28 To date, there are no human intervention trials that have tested I3C as a preventive or therapeutic agent against breast cancer. Cervical Cancer In a 12-week, double-blind study, eight of 17 patients with early-stage cervical cancer given 200 or 400 mg of I3C per day experienced a complete reversal of their conditions.29 Animal studies have also shown that I3C can help prevent cervical cancer in the presence of various carcinogens.30-31 Respiratory Tract Papillomas I3C supplementation reduced or halted the formation of papillomas (precancerous lesions) in 12 out of 18 patients with recurrent respiratory tract papillomas in a small trial.32 Prostate Cancer In animal studies, the ingestion of I3C has been shown to inhibit the growth of PC-3-type human prostate cancer cells by arresting their cell division cycle and by promoting apoptosis (programmed cell death).8 A Seattle study of male residents indicated that men consuming three or more servings per week of cruciferous vegetables had a 50-percent lower risk of prostate cancer than men consuming fewer servings, after controlling for other confounding variables.33 To date, no human intervention trials have tested I3C as a preventive or therapeutic agent against prostate cancer. Adverse Side Effects and Toxicity At doses of 800 mg per day, I3C has caused dizziness and unsteady gait (signs of nervous system toxicity) in humans and in animal studies. It is also a powerful stimulator of phase I detoxification enzymes, and may speed up the detoxification of certain medications, changing their required dosage. However, one challenge study revealed that I3C intake did not interfere with oral contraceptive medications.33 Nevertheless, health practitioners and patients should monitor their responses to I3C supplementation if taken at therapeutic doses concurrently with other drugs. According to animal studies, this appears to be especially true:33 testosterone replacement therapy; oral contraceptives; hormone replacement therapy; anti-seizure medications; immune-suppressant and antiviral drugs; and digoxin Drug-Nutrient Interactions Antacids and Heartburn Medications (H-2 antagonist drugs) These drugs reduce the absorption of I3C by reducing stomach acidity, and should not be taken at the same time of day or at the same meal.33 More Rapid Detoxification of Other Drugs As stated earlier, I3C may speed up the detoxification of any number of drugs, due to its stimulation effect of phase I detoxification centers. Patient monitoring is required with I3C supplementation at the therapeutic doses mentioned previously (300-400 mg per day).33 Summary and Conclusion Despite the lack of extensive human intervention trials, the overall body of evidence strongly suggests that I3C (and possibly other nutrients in cruciferous vegetables) acts through various biological means to help defend against certain cancers, particularly reproductive cancers in women and men. Given our high exposure to environmental toxins, additives, pollutants and contaminants that find their way into our body from food, water and air, it is of great importance to realize that I3C ingestion can help to optimize the body's detoxification, reducing the potential damage and carcinogenic effects of many of these exogenous agents. The phytoestrogen effects of I3C have been well studied, and appear to account for much of its ability to prevent reproductive cancers in animals. Based upon numerous animal experiments, human epidemiological studies, treatment of cervical cancer patients with I3C supplementation, and studies in humans evaluating the influence of I3C on estrone metabolism, it appears likely that I3C may be one of the most important cancer protective nutrients discovered to date. In my view, health practitioners should encourage patients to consume at least three servings per week of cruciferous vegetables and consider ingesting 30-60 mg of I3C as part of a cancer-prevention-and-detoxification-booster- supplement cocktail. A growing number of such supplements are now available in the marketplace because of the growing scientific understanding of the important biological activities exhibited by I3C. References Hecht SS. Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. J Nutr 1999;129:7688-74S. Verhoeven DT, Goldbohm RA, van Poppel G, et al. A review of mechanisms underlying anticarcinogenicity by Brassica vegetables. Chem Biol Interact 1997;103:79-129 (review). Verhoeven DT, Goldbohm RA, van Poppel G, et al. Epidemiological studies on Brassica vegetables and cancer risk. Cancer Epidemiol Biomarkers Prev 1996;5:733-48 (review). Talaley P, Zhang Y. Chemoprotection against cancer by isothiocyanates and glucosinolates. Biochem Soc Trans 1996;24:806-10. Maheo L, Morel F, Langouet S, et al. Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and rat hepatocytes. Cancer Res 1997;57:3649-52. Barcelo S, Gardiner JM, Gescher A, Chipman JK. CYP2E1-mediated mechanism of anti-genotoxicity of the broccoli constituent sulforaphane. Carcinogenesis 1996;17:277-82. Plumb GW, Lambert N, Chambers SJ, et al. Are whole extracts and purified glucosinolates from cruciferous vegetables antioxidants? Free Radic Res 1996;25:75-86. Dhinmi SR, Li Y, Upadhyay S, Koppolu PK, Sarkar FH. Indole-3-carbinol-induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene May 24, 2001;20(23):2927-36. Stoewsand GS. Bioactive organosulfur phytochemicals in Brassica oleracea vegetables — a review. Food Chem Toxicol 1995;33:537-43. Broadbent TA, Broadbent HS. The chemistry and pharmacology of I3C (indole-3-methanol) and 3-(methoxymethyl) indole (part I). Curr Med Chem 1998;5:337-52. Broadbent TA, Broadbent HS. The chemistry and pharmacology of I3C (indole-3-methanol) and 3-(methoxymethyl) indole (part II). Curr Med Chem 1998;5:469-91. Broadbent, T.A., Broadbent, H.S. The chemistry and pharmacology of I3C (indole-3-methanol) and 3-(methoxymethyl) indole (part I). Curr Med Chem 1998;5:337-52. Broadbent TA, Broadbent HS. The chemistry and pharmacology of I3C (indole-3-methanol) and 3-(methoxymethyl) indole. (part II). Curr Med Chem 1998;5:469-91. Beecher CW. Cancer preventive properties of varieties of Brassica oleracea: A review. Am J Clin Nutr May1994;59(5 suppl):1166S-1170S. Loub WD, et al. Aryl hydrocarbon hydroxylase induction in rat tissues by naturally occurring indoles of cruciferous plants. JNCI 1975;54:985-988. McDanell R, et al. Differential induction of mixed-function oxidase (MFO) activity in rat liver and intestine by diets containing processed cabbage. Food chem Toxicol 1987; 25:363-368. Hendrich S. and Bjeldanes LF. Effects of dietary cabbage, Brussels sprouts, Ilicium verum, Schizandra chinensis and alfa alfa on the benzopyrene metabolic enzyme system in mouse liver. Food Chem Toxicol 1983;21:479-486. Osborne MP, et al. Increase in the extent of estradiol 16-alpha-hydroxylation in human breast tissue: A potential biomarker of breast cancer risk. JNCI 1993;85:1917-20. Michnovicz JJ. Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. Int J Obes Relat Metab Disord 1998;22:227-9. Bradlow HL, Michnovicz JJ, Halper M, et al. Long-term responses of women to indole-3-carbinol or a high-fiber diet. Cancer Epidemiol Biomarkers Prev 1994;3:591-5. Tiwari RK, et al. Selective responsiveness of human breast cancer cells to indole-3-carbinol, a chemopreventive agent. JNCI 1994;86(2):126-31. Stoewsand GS, et al. Protective effects of dietary Brussels sprouts against mammary carcinogenesis in Sprague-Dawley rats. Cancer Lett 1988;39:199-207. Michnovicz JJ, Bradlow HL. Induction of estradiol metabolism by dietary indole-3-carbinol in humans. JNCI 1990;82:947-949. Bradfield CA, Bjeldanes LF. Effect of dietary indole-3-carbinol on intestinal and hepatic monooxygenase, gluatathione-S-transferase and epoxide hydrolase activities in rat. Food Chem Toxicol 1984;22:977-982. Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Indole-3-carbinol: A novel approach to breast cancer prevention. Ann NY Acad Sci 1999;889:204-13. Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Indole-3-carbinol: A novel approach to breast cancer prevention. Ann NY Acad Sci 1995;768:180-200. Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent. Ann NY Acad Sci 1999;889:204-13. Meng Q, Qi M, Chen DX, et al. Suppression of breast cancer invasion and migration by indole-3-carbinol: Associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med 2000;78:155-65. Bell MC, Crowley-Nowick P, Bradlow HL, et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol 2000:78;123-9. Yuan F, Chen DZ, Liu K, et al. Anti-estrogenic activities of indole-3-carbinol in cervical cells. Implication for prevention of cervical cancer. Anticancer Res 1999;19(3A):1673-80. Jin L, Qi M., Chen DZ, et al. Indole-3-carbinol prevents cervical cancer in human papilloma virus type-16 (HPV16) transgenic mice. Cancer Res 1999;59:3991-7. Rosen CA, Woodson GE, Thompson JW, et al. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg 1998;118:810-15. Zeligs M. The cruciferous choice. Townsend Letter for Doctors & Patients, Aug/Sept 2001;217/218:47-48. Sabinsa Corporation. Indole-3-Carbinol Product Manual (www.sbinsa.com). James Meschino, DC, MS Toronto, Ontario, Canada www.renaisante.com Fighting Prostate Cancer with Broccoli Compounds Dietary indoles found in cruciferous vegetables are beneficial for both men and women By Dr. Edward R. Rosick It seems to be the prerogative of youth to think of advice given to them by their elders as generally useless and annoying. This is especially true when it comes to dietary choices—how vividly I recall my grandmother telling me that if I wanted to grow up big and strong, I needed to eat such distasteful foods (at least to my youthful sensibilities) as broccoli, cauliflower, and cabbage in the form of sauerkraut. Looking back (and going through my own battles to get my children to eat a semi-healthy diet), I sometimes wonder why my grandparents thought the way they did. What was passed down, generation after generation, that made them know almost instinctively that cruciferous vegetables, such as broccoli, cauliflower, cabbage, kale, and Brussels sprouts, are important for good health? -------------------------------------------------------------------------------- I3C causes cell death in breast cancer cells but not in noncancerous breast cells. -------------------------------------------------------------------------------- Although my grandparents are sadly no longer around to answer that question, there is now an impressive body of data showing that certain chemical compounds in cruciferous vegetables can protect men from prostate cancer, the second leading cause of cancer death among American men. This is but one example illustrating the age-old wisdom that eating a well-balanced diet full of fruits and vegetables is good for us. Let’s look at some of the evidence. Cruciferous Vegetables Reduce Risk of Prostate Cancer Two large studies published in 2000 showed that men who had a diet high in cruciferous vegetables had a statistically significant reduction in the risk of prostate cancer.1,2 In one of these studies, there was a remarkable 41% risk reduction among men who ate three or more servings of cruciferous vegetables per week, as compared to men eating fewer than one serving per week, even after the researchers controlled for all other vegetable intake.1 This led the researchers to conclude that “. . . the substitution of cruciferous vegetables for other vegetables, while keeping total vegetable intake constant, significantly reduces prostate cancer risk.” Clearly, cruciferous veggies should make regular appearances on the dinner plates not only of children who want to grow up big and strong, but also of their fathers and grandfathers—and of their mothers and grandmothers too. Studies have shown that women who have diets high in cruciferous vegetables have a reduced risk of developing breast cancer.3 I3C May Fight Breast and Cervical Cancer It is now thought that one of the principal cancer-fighting constituents of cruciferous vegetables is a compound called indole-3-carbinol, or I3C for short. Two other compounds that also contribute a potent punch are very closely related to I3C. One is 3,3’-diindolylmethane (DIM), which is a dimer of I3C (i.e., two I3C molecules joined by a chemical bond), and the other is ascorbigen, which is an I3C molecule joined by a chemical bond to a molecule of vitamin C (ascorbic acid). Collectively, these three compounds are called dietary indoles (an indole being a certain type of organic compound). -------------------------------------------------------------------------------- I3C can inhibit the replication of human papilloma virus, a known cause of cervical cancer. -------------------------------------------------------------------------------- In animal studies examining chemically induced mammary tumors, all three of these compounds have been shown to reduce the number of tumors per animal.4 More recent work has shown that I3C causes cell death in breast cancer cells but not in noncancerous breast cells.5 Yet other studies on cell cultures have shown that I3C can inhibit the replication of human papilloma virus, a known cause of cervical cancer.4 Estrogens: The Good and the Bad Although the manner in which the dietary indoles protect against cancer is not entirely clear, a possible mechanism involves their actions on the hormone estrogen (which is actually not just one compound, but several related ones that have similar biological activities). Estrogen, which gives women their secondary sex characteristics, has only recently been discovered to be important in a number of physiological functions in men as well, including maintenance of bone mass and cognitive functions.6 In women the majority of estrogen is produced by the ovaries, whereas in men it is produced primarily through the chemical conversion of androgenic (male) hormones by aromatase, an enzyme found in epithelial, fat, bone, and brain cells. Although some estrogen is essential to health in men (just as some testosterone is essential to health in women), too much of it can be harmful in both men and women, especially when it’s in the form of 16-alpha-hydroxyestrone. This compound, a product of estrogen metabolism, has high estrogenic activity and has been implicated in breast and cervical cancers (it’s called “bad estrogen”). A related estrogen metabolite, 2-hydroxyestrone, has low estrogenic activity and is believed to be much less harmful (it’s called “good estrogen”). Thus, the higher the ratio of 2-hydroxyestrone to 16-alpha-hydroxyestrone, the better. Does Estrogen Cause Prostate Cancer? Ask almost any mainstream physician what causes prostate cancer, and chances are the answer will be testosterone. This is based on research showing that castration, either physically or through chemical means, slows (but does not cure) prostate cancer. However, a growing number of doctors and researchers believe that estrogen and its metabolites, notably 16-alpha-hydroxyestrone, may be a significant factor in the development of prostate cancer. This idea is based on the fact that, while testosterone levels are highest in young men, prostate cancer is a disease almost exclusively of older men, who have lower levels of testosterone but higher levels of estrogen than younger men. A recent article in the World Journal of Urology sums up the estrogen/prostate cancer issue succinctly: “Estrogenic stimulation through estrogen receptor alpha in a milieu of decreasing androgens [testosterone] contributes significantly to the genesis of benign prostatic hyperplasia, prostate dysplasia, and prostate cancer.”7 Dietary Indoles Improve the Estrogen Ratio One of the ways in which I3C, DIM, ascorbigen, and other phytochemicals found in cruciferous vegetables may fight cancer is through their action on estrogen and its metabolites. Studies have demonstrated that I3C increases the amount of 2-hydroxyestrone relative to the amount of 16-alpha-hydroxyestrone, thereby increasing the ratio of “good estrogen” to “bad estrogen”—a very good thing for both men and women. For men, this could mean a decrease in the risk of prostate cancer. In a recent study that examined the association of this risk with estrogen metabolism, the authors stated that “Results of this case-control study suggest that the estrogen metabolic pathway favoring 2-hydroxylation over 16-alpha-hydroxylation may reduce the risk of clinically evident prostate cancer.”8 (Hydroxylation is the chemical process that leads to the estrogen metabolites in question.) Dietary Indoles Kill Prostate Cancer Cells With earlier work showing the effectiveness of I3C in preventing animal tumors, along with epidemiological studies showing that men who have a diet high in cruciferous vegetables have a decreased risk of prostate cancer, scientists are now examining the cellular mechanisms by which dietary indoles protect against prostate cancer. In one such study, researchers exposed human prostate cancer cells to either I3C or DIM for 48 hours to examine their effects on cell proliferation.9 The researchers also studied the effects of I3C and DIM on the induction of apoptosis (cell death) in these cells. Both results were encouraging: the proliferation of prostate cancer cells was significantly reduced when they were exposed to I3C or DIM, and both of these agents caused apoptosis of the cells. A similar study looked at the effects of using I3C as an adjunct to prostate cancer therapy with a substance called (get ready for this) tumor necrosis factor-related apoptosis-inducing ligand, mercifully known as TRAIL for short.10 TRAIL is a low-toxicity anticancer drug that has shown promise in inducing apoptosis in prostate cancer cells. It was found that I3C, even at very low doses, potentiated the prostate cancer-killing ability of TRAIL. Dietary Indoles Are Well Tolerated Although eating cruciferous vegetables regularly is fine and healthy,* it is not always possible—or it’s just plain inconvenient—to get the optimal amounts of the dietary indoles in this way. The answer to that, of course, is supplementation, but it behooves us to know the long-term effects of taking these compounds on a daily basis. -------------------------------------------------------------------------------- *It is sometimes alleged that eating too many cruciferous vegetables can lead to goiter (an enlarged thyroid gland), but this claim is overblown. One would have to eat very large amounts regularly, and one would almost have to have an iodine deficiency to begin with, which has been virtually unheard of in the developed world since iodized salt was introduced in the 1920s. -------------------------------------------------------------------------------- A recent study looked at the effects of high doses of I3C and DIM in rats over 3-month and 12-month periods.11 The results were encouraging: even though the animals were given the equivalent of seven times (in the case of I3C) to ten times (in the case of DIM) the recommended daily doses of these supplements for humans, there were no significant differences in blood chemistry between the animals in the 3-month and 12-month groups, leading the authors to conclude that “The data from this study confirm results from short-term studies indicating that both I3C and DIM are relatively nontoxic compounds.” Dietary Indole Supplements Are the Way to Go It’s wise to remember that laboratory and animal studies such as the ones discussed in this article are no substitute for clinical trials and cannot be regarded as the final word on the effects of the dietary indoles in humans. They do, however, provide a growing basis for confidence that these compounds are safe, nontoxic substances that may very well provide significant protection against prostate, breast, and cervical cancers. Although the admonishment to “eat your veggies” is right on the money, especially where the cruciferous vegetables are concerned, the most reliable way to get the benefits of these highly healthful foods is in the convenient form of dietary indole supplements, which can help you optimize that important estrogen ratio we talked about. References Cohen JH, Kristal AR, Stanford JL. Fruit and vegetable intakes and prostate cancer risk. J Natl Cancer Inst 2000;92(1):61-8. Kolonel LN et al. Vegetables, fruits, legumes, and prostate cancer: a multiethnic case-control study. Cancer Epidemiol Biomark Prev 2000;9: 795-804. Freudenheim JL et al. Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients. J Natl Cancer Inst 1996;88:340-8. PDR for Nutritional Supplements, Medical Economics Co., Montvale, NJ, 2001, pp 218-20. Rahman KMW, Aranha O, Sarkar FH. Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells. Nutr Cancer 2003;45(1):101-12. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Derm 2001;45(3):116-24. Steiner MS, Raghow S. Antiestrogens and selective estrogen receptor modulators reduce prostate cancer risk. World J Urol 2003;21(1):31-6. Muti P et al. Urinary estrogen metabolites and prostate cancer: a case-control study in the United States. Cancer Causes Control 2002;13(10): 947-55. Nachshon-Kedmi M, Yannai S, Haj A, Fares FA. Indole-3-carbinol and 3,3’-diindolylmethane induce apoptosis in human prostate cancer cells. Food Chem Toxicol 2003;41:745-52. Jeon K-I et al. Pretreatment of indole-3-carbinol augments TRAIL-induced apoptosis in a prostate cancer cell line, LNCaP. FEBS Lett 2003;544:246-51. Leibelt DA et al. Evaluation of chronic dietary exposure to indole-3-carbinol and absorption-enhanced 3,3’-diindolylmethane in Sprague-Dawley rats. Toxicol Sci 2003;74:10-21 Human Growth Hormone (HGH), Testosterone & Male Menopause (Andropause) Medical Information Sponsored by the Cenegenics® Medical Institute Home Page | Human Growth Hormone (HGH) | Testosterone | Physician Information | Male Menopause (Andropause) | Cenegenics® CAN A CABBAGE A DAY KEEP CANCER AWAY? If you are a woman, you should be concerned about breast cancer. If you are a man, you should be concerned about prostate cancer. And if you are concerned about either breast cancer or prostate cancer, you should know that eating cruciferous vegetables, such as broccoli and cabbage, is really good for you. Eating half of a head of cabbage each day or extremely large amounts of other cruciferous vegetables is what it would take to get the kind of health risk reduction you're looking for--and that is neither practical nor palatable. But, if science could separate the cancer fighting substance in the vegetables and pack them into a pill or capsule, it might actually help save your life. That is precisely what has happened. What is Indole-3-Carbinol (I3C)? The indole group of sulfur compounds binds to chemical carcinogens and activates enzymes that, in turn, detoxify those chemical carcinogens. Indole-3-Carbinol (I3C) is a phytonutrient that occurs naturally in certain cruciferous vegetables, appearing to affect estrogen metabolism in ways that might help prevent breast cancer, and Indole-3-Carbinol may also be critical in preventing or retarding prostate cancer. I3C is the specific phytonutrient that has been shown to act as a catalyst to pull estradiol down a benign pathway to 2-hydroxyestrone. After isolating I3C, scientists have been able to prepare nutraceuticals of I3C at the proper physiologic dose to help prevent both breast cancer in women and prostate cancer in men; therefore, every non-pregnant woman and every man should consider taking pharmacy grade I3C as part of his or her daily nutraceutical regimen for disease prevention. What does Indole-3-Carbinol do? In 1991 researchers at the Institute for Hormone Research in New York City proved that I3C significantly reduced the incidence and, in fact, the number of tumors in female mice prone to developing breast cancer. In human studies, levels of "strong" estrogen declined and levels of "weak" estrogen increased, and, most important, there was a marked decrease in the level of the estrogen metabolite associated with breast and endometrial cancer (16alpha-hydroxyestrone). Furthermore, I3C fits into the aryl hydrocarbon (Ah) receptor, but according to researchers at Texas A&M, unlike the toxic chemical Dioxin that also activates the Ah receptor, I3C not only positively affects estrogen metabolism, I3C also can keep Dioxin out of the cells. But if I3C alters estrogen metabolism, how can it be effective in preventing or even retarding prostate cancer? When the cancer cell is stopped at the checkpoint, the body has more of a chance to destroy it before it can grow. It is the balance of hormone cells in prostate cancer that is important rather than the level of any particular hormone. So, how is it possible for I3C to be effective against prostate cancer? The answer is that its effectiveness against prostate cancer comes from the other anti-cancer properties that I3C contains. Indole-3-Carbinol has been shown to force cancer cells to stop at "checkpoints" (like a normal, healthy cell does before replicating). It also has the potential to help restore communication to the sex hormones through the Ah receptor, discussed above. In prostate cancer, sex hormone cells cannot communicate normally, telling other cells to do things, like grow. It appears that I3C is one of only a few substances that have the ability to restore communications. Will Indole-3-Carbinol absolutely prevent breast cancer or stop or retard prostate cancer? No one knows for sure, but current government studies are extremely promising. The problem seems to be that these studies are too limited in scope (less than 250 women), and lacking the hundreds of millions of dollars that has gone into the research and development of synthetic chemicals, such as Tamoxifen. Can it be that the money for Research and Development is more likely to go to drugs on which companies can claim patents, rather than on such natural substances as that which can be found in a head of cabbage? In the meantime, since the American Cancer Society has advised men to reduce their risk of prostate cancer by increasing their intake of cruciferous vegetables, and research, such as the 1998 study from the University of California at Berkeley , have shown that Indole-3-Carbinol was 30% more effective than Tamoxifen in inhibiting the growth of estrogen receptor-positive breast cancer cells, it would be wise to take heed to what your grandmother used to tell you: "Eat your vegetables. They're good for you!" Indole-3-Carbinol and the 2/16a-hydroxyestrone ratio According to Dr. Barnett Zumoff "an impressive and consistent body of studies since 1966 has made it clear that increased 16a-hydroxylation of estradiol is associated with breast cancer and risk for breast cancer in both mice and humans…" There are three down stream products of metabolism (metabolites) of estradiol: 16-alphahydroxyestrone, 4-hydroxyestrone, and 2-hydroxyestrone. It is the 16-alphahydroxy-estrone that has been shown to be carcinogenic in animal and invitro studies. The 16-alphahydroxyestrone is sometimes called "strong" estrogen. The "weak" or benign estrogen is the 2-hydroxyestrone. Indole-3-Carbinol catalyzes the reaction of estradiol to 2-hydroxyestrone. Therefore there is an increase in 2-hydroxyestrone and a decrease in 16-alphahydroxyestrone, resulting in a commensurate lowering of the risk of breast cancer. The results of a 1996 placebo controlled double-blind study of 57 healthy, adult women at increased risk for breast cancer, suggests that Indole-3-Carbinol is an extremely promising agent for the prevention of breast cancer . A 1997 study noted that I3C not only stopped 54-61% of the human cancer cells from growing, but also actually provoked the cells to self-destruct . The Ah Receptor and Dioxin Dioxin is a toxic chemical made from chlorine. It is insidious and tenacious, and unfortunately, pervasive. Dioxin can be found in pesticides, wood preservatives, Saran Wrap®, and has even been detected in McDonald's Big Macs®, Haagen-Daz® ice cream, Kentucky Fried Chicken®, meat, dairy products, and fish, because every time plastic is burned or paper is bleached, Dioxin is released into the environment. It lodges in fat and is extremely difficult to remove. In some studies it has been associated with increased incidence of breast cancer, although not all studies reach that conclusion. What is agreed, however, is that even trace amounts of Dioxin can be deadly. Like I3C, Dioxin affects estrogen metabolism through the Ah Receptor; but they each send very different signals. Dioxin activates cancer genes and holds back the genes that suppress tumors; and it disrupts insulin-like growth factors (IGF-1) and tumor necrosis factor (NGF)-important growth regulatory factors. The National Institute of Environmental Health Sciences was among several research centers establishing one of the fundamental mechanisms of dioxin toxicity, the Ah Receptor. Like Dioxin, Indole-3-Carbinol also fits into the Ah Receptor, but it sends messages that are the antithesis of Dioxin. I3C sends out messages that are detrimental to cancer growth and beneficial to estrogen metabolism. I3C interrupts cell cycles, like the Tamoxifen, and restores tumor suppressors, where Tamoxifen does not. Furthermore, studies using I3C in animals prior to exposing them to certain carcinogens, showed that I3C virtually eliminate the damage that would have been expected. While this article is concentrating on breast cancer and prostate cancer, there have been a number of promising studies using I3C to help prevent lung, liver, and ovarian cancer. Additional references: i. Arnao MB (1996): "Indole-3-carbinol as a scavenger of free radicals." Biochem Mol Biol Int 39:1125-34. ii. Barakat et al (1997): "Evaluation of p53, Bcl-2, and c-Ki-ras status in endometrial cnacers occurring after breast cancer with or without tamoxifen treatment" (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol 16:AI289. iii. Bradlow et al (1985): "Estradiol 16a-hydroxylation in the mouse correlates with mammary tumor incience and presence of murine mammary tumor virus: A possible model for the hormonal etiology of breast cancer in humans." Porc Natl Acad Sci USA 82:6295-6299. iv. Bradlow et al (1991): Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis 12:1571-1574. v. Bradlow et al (1994): "Long-term responses of women to indole-3-carbinol or a high fiber diet." Cancer Epidemiol Biomarkers Prev 3:591-595. vi. Bradlow et al (1996): "2-Hydroxyestrone: the "good" estrogen." J Endocrinol 150:S259-S265. vii. Bradlow et al (1996): "Indole-3-carbinol: a novel approach to breast cancer prevention." Ann NY Acad Sci 768:180-200. viii. Bradlow et al (1998): "Application of an improved ELISA assay to the analysis of urinary estrogen metabolites." Steroids (in press). ix. Chen et al (1996): "Indole-3-carbinl and di-indolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells." Biochem Pharmacol 51:1069-76. x. Chen et al (1998): "Aryl hydrocarbon receptor-mediated antiestrogenic and anti-immunogenic activity of di-indolylmethane." Carcinogenesis 19:163-9. xi. Ferlini et al (1999): "Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines." Br J Cancer 79:257-63. xii. Firestone, Gary L (2000-2001): "Indole Derivatives as Novel Breast Cancer Therapeutics," Nutrition and Healing; U Cal, Berkeley, ongoing study. xiii. Grubbs et al (1995): "Chemoprevention of chemically induced mammary carcinogenesis by indole-3-carbinol." Anti-Cancer Res 15:709-716. xiv. Gundimeda et al (1996): "Tamoxifen modulates protein kinase C via oxidative stress in estrogen receptor-negative breast cancer cells." J Biol Chem 271:12504-14. xv. Manz, et al. "Cancer mortality among workers in chemical plant contaminated with dioxin." Lancet 338:959-64. xvi. Michnovicz JJ, Bradlow HL (1990): "Induction of estradiol metabolism by dietary indole-3-carbinol in humans." JNCI 82:947-949. xvii. Michnovicz et al (1991): "Changes in levels of urinary estrogen metaoblites after oral I3C treatment in humans." J Natl Cancer Inst 89:718-23. xviii. Niwa et al (1994): "Alterations in estradiol metabolism in MCF-7 cells induced by treatment with indole-3-carbinol and related compounds." Steroids 58:523-527. xix. Osborne et al (1988): "Omega-3 fatty acids: Modulation of estrogen metabolism and potential for breast cancer." Cancer Invest 6:629-631. xx. Sharma et al (1994): "Screening of potential chemopreventive agents using biochemical markers of carcinogenesis." Cancer Res 54:5848-55. xxi. Suto et al (1993): "Experimental down-regulation of intermediate biomarkers of carcinogenesis in mouse mammary epithelial cells." Breast Cancer Res Treat 27:193-202. xxii. Taoli et al (1998): "Cyp1A1 geotpe, estradiol metabolism and breast cancer in African Americans." Cancer Prev Detect (in press). xxiii. Telang et al (1992): "Induction by estrogen metaolite 16a-hydroxylation of genotoxic damage and aberrant proligeration in mouse mammary epithelial cells." JNCI 84:634-636. xxiv. Tiwari et al (1994): "Selective responsiveness of human breast cancer cells to indole-3-carbinol, a chemoprevetive agent." JNCI 86:126-131. xxv. Verhoeven et al (1996): "Epidemiological studies on brassica vegetables and cancer risk." Cancer Epidemiol Biomarkers Prev 5:733-748. xxvi. Wattenberg LW, Loub WD (1978): "Inhibition of polycyclic aromatic hydrocarbon induced neoplasia by naturally occurring indoles." Cancer Res 38:1410-1413. xxvii. Wright, Jonathan, M.D. "Reducing the hormone related cancer risk/or cabbages, sex hormones, and their metabolites," Nutrition and Healing USA. xxviii. Zimmerman, Marcia (2000): "Phytochemicals: nutrients whose time has come," Nut Sci News.     < BACK TO HEADLINES

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