Comprehensive Guide to Indole-3-Carbinol

Indole-3-CarbinolDr. James Meschino DC, MS, ND
Download in PDF format Download in Epub format Download in Kindle format
General Features
Indole-3-Carbinol has been shown to be one of the major anti-cancer substances found in cruciferous vegetables. Frequent consumption of these vegetables (broccoli, cauliflower, cabbage, Brussels sprouts, kale and bok choy) is associated with reduced risk of cancer in many human and animal studies.1-8 Indole -3-Carbinol is a member of the class of sulfur-containing chemicals called glucosinolates (previously called thioglucosides).9 It is formed by the action of myrosinase enzyme acting on the parent compound glucosinolates, whenever cruciferous vegetables are crushed (e.g., chewing) or cooked.10,11 Indole-3-Carbinol and other glucosinolates (e.g., other indoles and isothiocyanates such as sulforphane) are antioxidants and potent stimulators of Phase I and Phase II detoxification enzymes in the liver and intestinal epithelial cells.12,13,14 In this capacity it helps the body more easily eliminate toxic compounds, including many carcinogens.15,16,17 Indole-3-Carbinol also acts as a phytoestrogen (plant-based estrogens) and, in this capacity, can bind to estrogen receptors in the body, reducing the ability of stronger estrogens from over stimulating reproductive tissues such as the breast, cervix, uterus, and in males, the prostate gland. In this regard, the ingestion of Indole-3-Carbinol is highly associated with the prevention of reproductive organ cancers in women and men.3,4,8 It also 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.18,19,20 Thus far, human studies have used a dose of 300-400 mg per day to demonstrate this outcome
Clinical Application and Mechanism of Action
1. Prevention of Female Reproductive Cancers
In experimental animal testing with mice and rats, Indole-3-Carbinol and brussels sprouts, respectively, have demonstrated an ability to reduce mammary cancer incidence in animals exposed to carcinogens that are known to promote mammary cancer in these species.21,22 In human studies, the ingestion of Indole-3-Carbinol has been shown to increase the metabolism of estrone hormone to 2-hydroxyestrone rather than the16-alpha-hydroxyestrone metabolite. Studies indicate that 16-alpha-hydroxyestrone is associated with an increased risk of breast cancer in women and, conversely, 2-hydroxyestrone is associated with a reduction in breast cancer risk. Thus, Indole-3-Carbinol influences the body’s enzyme systems in a fashion that favorably influences the 2-hydroxyestrone to 16-alpha-hydroxyestrone 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 2/16 hydroxyestrone ratio to predict which women were less prone to breast cancer development.
a. Breast Cancer: Epidemiological studies and experimental evidence strongly suggests that Indole-3-Carbinol may reduce breast cancer risk through the above-cited mechanisms.25,26,27,28 To date there are no human intervention trials that have tested Indole-3-Carbinol as a preventive or therapeutic agent against breast cancer.
b. Cervical Cancer: In a 12-week double-blind study, 8 of 17 patients with early-stage cervical cancer given 200 or 400 mg of Indole-3-Carbinol per day experienced a complete reversal of their condition.29 Animal studies have also shown that indole-3-carbinol can help prevent cervical cancer in the presence of various carcinogens.30,31
2. Respiratory Tract Papillomas
Indole-3-Carbinol 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.
3. Prostate Cancer
In animal studies, the ingestion of Indole-3-Carbinol 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 men living in that city indicated that men consuming three or more servings per week of cruciferous vegetables had a risk of prostate cancer that was 50% lower than men consuming fewer servings of these vegetables, after controlling for other confounding variables.33 To date there no human intervention trials have tested Indole-3-Carbinol as a preventive or therapeutic agent against prostate cancer.
Dosage and Standardized Grade
1. General Health Maintenance: 25-100 mg per day
2. Therapeutic Applications: 300-400 mg per day
Adverse Side Effects, Toxicity and Contraindications
At doses of 800 mg per day, Indole-3-Carbinol has caused dizziness and unsteady gait (signs of nervous system toxicity) in humans and in animal studies. As well, Indole-3-Carbinol is a powerful stimulator of phase I detoxification enzymes, and as such, it may speed up the detoxification of certain medications, changing their required dosage. However, one challenge study of this kind revealed that Indole-3-Carbinol intake did not interfere with oral contraceptive medications.33 Nevertheless, health practitioners and patients should monitor their response to Indole-3-Carbinol supplementation, if taken at therapeutic doses concurrently with other drugs. According to animal studies, this appears to be especially true in regards to the following medications:
testosterone replacement therapy
oral contraceptives
hormone replacement therapy
anti-seizure medications
immune-suppressant and anti-viral drugs
digoxin
Drug-Nutrient Interactions
1. Antacids and Heartburn medications (H-2 antagonist drugs ): By reducing stomach acidity these drugs reduce the absorption of indole-3-carbinol. Therefore, they should not be taken at the same time of day or at the same meal.33
2. More Rapid Detoxification Of Other Drugs: As stated above, Indole-3-Carbinol may speed up the detoxification of any number of drugs due to its stimulation affect on phase I detoxification centers. Thus, patient monitoring is required with Indole-3-Carbinol supplementation at the therapeutic doses mentioned previously (300-400 mg per day).
Pregnancy and Lactation
During pregnancy and lactation, the only supplements that are considered safe include standard prenatal vitamin and mineral supplements. All other supplements or dose alterations may pose a threat to the developing fetus and there is generally insufficient evidence at this time to determine an absolute level of safety for most dietary supplements other than a prenatal supplement. Any supplementation practices beyond a prenatal supplement should involve the cooperation of the attending physician (e.g., magnesium and the treatment of preeclampsia.)

References: Pregnancy and Lactation
1. Encyclopedia of Nutritional Supplements. Murray M. Prima Publishing 1998.
2. Reavley NM. The New Encyclopedia of Vitamins, Minerals, Supplements, and Herbs. Evans and Company Inc. 1998.
3. The Healing Power of Herbs (2nd edition). Murray M. Prima Publishing 1995.
4. Boon H and Smith M. Health Care Professional Training Program in Complementary Medicine. Institute of Applied Complementary Medicine Inc. 1997.
References
1. Hecht SS. Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. J Nutr, 1999;129:7688-94S
2. 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]
3. 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]
4. Talaley P, Zhang Y. Chemoprotection against cancer by isothiocyanates and glucosinolates. Biochem Soc Trans, 1996;24:806-10
5. 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
6. Barcelo S, Gardiner JM, Gescher A. Chipman JK. CYP2E1-mediated mechanism of anti-genotoxicity of the broccoli constituent sulforaphane. Carcinogenesis, 1996;17:277-82
7. 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
8. Dhinmi SR, Li Y, Upadhyay S, Koppolu PK, Sarkar FH. Indole-3-carbinol (I3C) – induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene, 24May2001;20(23):2927-36
9. Stoewsand GS. Bioactive organosulfur phytochemicals in Brassica oleracea vegetables – a review. Food Chem Toxicol, 1995;33:537-43
10. Broadbent TA, Broadbent HS. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl) Indole. [Part I]. Curr Med Chem, 1998;5:337-52
11. Broadbent TA, Broadbent HS. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl) Indole. [Part II]. Curr Med Chem, 1998;5:469-91
12. Broadbent TA, Broadbent HS. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl) Indole. [Part I]. Curr Med Chem, 1998;5:337-52
13. Broadbent TA, Broadbent HS. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl) Indole. [Part II]. Curr Med Chem, 1998;5:469-91
14. Beecher CW. Cancer preventive properties of varieties of Brassica oleracea: a review. Am J Clin Nutr, May1994;59(5suppl):1166S-70S
15. Loub WD, et al. Aryl hydrocarbon hydroxylase induction in rat tissues by naturally occurring indoles of cruciferous plants. JNCI, 1975;54:985-8
16. 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;25:363-8
17. Hendrich S. 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;21:479-86
18. 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
19. Michnovicz JJ. Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. Int J Obes Relat Metab Disord, 1998;22:227-9
20. 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
21. Tiwari RK., et al. Selective responsiveness of human breast cancer cells to indole-3-carbinol, a chemopreventive agent. JNCI, 1994;86(2):126-31
22. Stoewsand GS, et al. Protective effects of dietary Brussels sprouts against mammary carcinogenesis in Sprague-Dawley rats. Cancer Lett, 1988;39:199-207
23. Michnovicz JJ, Bradlow, H.L. (1990) Induction of estradiol metabolism by dietary indole-3-carbinol in humans. JNCI, 1990;82:947-9
24. 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;22:977-82
25. 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
26. 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
27. 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
28. Meng Q, Qi M, Chen D.X. 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
29. 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
30. 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
31. 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
32. 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;118:810-5
33. Zeligs M. The Cruciferous Choice. Townsend Letter for Doctors & Patients. Aug/Sept 2001, (217/218):p47-48
34. Sabinsa Corporation. Indole-3-Carbinol Product Manual (www.sabinsa.com)