Indole-3-Carbinol

Health Care Professional Information

Scientific Name
Indole-3-Methanol
Common Name

I3C, 1H-Indole-3-methanol, indole-3-methanol, 3-(Hydroxymethyl)indole, 3-indolylcarbinol, indolylmethanol

Brand Name

I3C Plus (Health Products Distributors)

Clinical Summary

Indole-3-Carbinol (I3C) is a compound found in cruciferous vegetables including broccoli, cabbage and cauliflower. Because diets high in these vegetables retard cancer growth in animals, I3C is thought to be a good candidate for cancer prevention (1).
Severa studies demonstrate that it can cause cell cycle arrest (6) (7) and apoptosis (8) (9) (10) (11) (12) in cancer cell lines, has antiangiogenic activity (22)and inhibits tobacco smoke-induced lung adenocarcinoma in mice (23). Studies also indicate that I3C enhances efficacy of gemcitabine (24) and acts synergistically with bortezomib (25) in vitro.

Data from clinical trials show that I3C is effective in treatment of precancerous cervical dysplasia (2) and vulvar intraepithelial neoplasia (3). In premenopausal women, a supplement containing I3C and 7-hydroxymatairesinol significantly increased the urinary 2:16-hydroxyestrone ratio, a known biomarker for the reduction of breast cancer risk (4).
I3C also stimulates detoxification enzymes in the gut and liver (5).

I3C is generally well tolerated when taken orally. But it may promote tumor growth in animals that have been exposed to carcinogens (13). Because it induces cytochrome P450 enzymes (14), I3C may interact with several medications.

Food Sources

Broccoli, brussels sprouts, cabbage, cauliflower, collards, kale, kohlrabi, mustard greens, rapeseed, rutabaga, and turnip.

Purported Uses
  • Cancer prevention
  • Detoxification
  • Viral infections
Mechanism of Action

Studies indicate that I3C has potential value as a chemopreventive agent for breast cancer through its estrogen receptor (ER) modulating effect (15). There is also evidence to support the fact that I3C has a different mechanism of action than tamoxifen and that these two can be used synergistically (6). An in vitro study also found that I3C reduces breast cancer cell migration and invasion by inhibiting matrix metalloproteinase (MMP)-2 expression and blocking extracellular signal-regulated kinase (ERK)/Sp1-mediated gene transcription (16). I3C also down-regulates the expression of the estrogen-responsive genes pS2 and cathepsin-D and up-regulates BRAC1 (17). Other in vitro studies show that I3C inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest independent of ER signaling (7). One randomized clinical trial suggests that I3C can increase the 2-OH-estrone to -estriol metabolite ratio (18). This is thought to decrease the risk of ER-sensitive breast cancer and cervical cancer. In human lung carcinoma A549 cells, I3C significantly reduced cell proliferation and induced apoptosis and cell cycle arrest at the G0/G1 phase (12). I3C also lowered the LD50 of gemcitabine (Gemzar) and decrease the growth of pancreatic cancer cells, possibly through reactivation of the tumor suppressor gene p16INK4a (19). Diindolylmethane (DIM), a metabolite of I3C, can induce apoptosis by modulating the expression of the Bax/Bcl-2 (10). I3C can cause apoptosis of prostate cancer cells in vitro by inhibition of Akt, activation (8). It also holds promise in preventing cancer with a papillomavirus component (20) (21).
I3C induces cytochrome P450 1 family, which may lead to potential drug interactions (14).

Pharmacokinetics

No published data regarding the pharmacokinetics of I3C in humans currently exists. Animal studies shows that I3C itself is not active. Gastric acid converts I3C to active metabolites diindolylmethane and indolylcarbazole, which are further metabolized in the liver. Most metabolites are excreted through the feces.
(6)

Adverse Reactions
  • Reported: Some patients experienced skin rash (5) (15).
  • I3C may promote tumor growth in animals exposed to carcinogens. However, this effect has not been confirmed in humans.

 

Herb-Drug Interactions
  • Cytochrome P450 1A2 substrates: I3C induces CYP 1A2 and can reduce serum concentration of medications metabolized by this enzyme (14).
Herb Lab Interactions
  • In rare cases, small increases in ALT have occured (5) (15).
Literature Summary and Critique

Laidlaw M, Cockerline CA, Sepkovic DW. Effects of a breast-health herbal formula supplement on estrogen metabolism in pre- and post-menopausal women not taking hormonal contraceptives or supplements: a randomized controlled trial. Breast Cancer. 2010 Dec 16;4:85-95.
This randomized, double-blind, placebo-controlled, parallel group study enrolled pre- (n=47) and post-menopausal (n=49) women who were not on contraceptives or hormone replacement therapy. Subjects were randomized to receive either treatment or placebo. A supplement containing 7-hydroxymatairesinol (HMR lignan) and indole-3 carbinol (I3C), along with other minor herbal constituents, was given to the treatment group. The placebo group received capsules containing microcrystalline cellulose. At baseline and study end (day 28), blood samples were analyzed for serum enterolactone concentrations, and morning urine samples were evaluated for estrogen metabolites. Pre-menopausal women receiving the HMR lignan/I3C upplement had a significant increase (p=0.003) in urinary 2-hydroxyestrone (2-OHE) concentrations and in 2:16á-OHE ratio (p=0.016). Post-menopausal women receiving the supplement had a significant increase in urinary 2-OHE concentrations (p=0.035). In the pre- and post-menopausal groups combined, a significant increase in urinary 2-OHE concentrations (p=0.001) and a trend (p=0.074) toward increased 2:16-OHE ratio were observed. The authors concluded that HMR lignan/I3C supplementation significantly increased estrogen C-2 hydroxylation, which may reduce the risk for breast and other estrogen-related cancers.

Dosage (Inside MSKCC Only)
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References
  1. Wattenberg LW, Loub WD. Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res 1978;38:1410-3.
  2. Bell MC, et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol 2000;78:123-9.
  3. Naik R, Nixon S, Lopes A, et al. A randomized phase II trials of indole-3-carbinol in the treatment of vulvar intraepithelial neoplasia. Int J Gynecol Cancer 2006;16(2):786-90.
  4. Laidlaw M, Cockerline CA, Sepkovic DW. Effects of a breast-health herbal formula supplement on estrogen metabolism in pre- and post-menopausal women not taking hormonal contraceptives or supplements: a randomized controlled trial. Breast Cancer. 2010 Dec 16;4:85-95.
  5. Indole-3-Carinol(I3C). National Toxicology Program. NIEHS. Accessed November 6, 2012.
  6. Cover CM, et al. Indole-3-carbinol and Tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Res 1999; 59:1244-51.
  7. Cover CM, et al. Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. J Biol Chem 1998;273:3838-47.
  8. Chinni SR, Sarkar FH. Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells. Clin Cancer Res 2002;8:1228-36.
  9. Chen DZ, et al. Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J Nutr 2001;131:3294-302.
  10. Hong C, et al. Bcl-2 family-mediated apoptotic effects of 3,3'-diindolylmethane (DIM) in human breast cancer cells. Biochem Pharmacol 2002 Mar 15;63(6):1085-97.
  11. Nachshon-Kedmi M, et al. Indole-3-carbinol and 3,3'-diindolylmethane induce apoptosis in human prostate cancer cells. Food Chem Toxicol 2003 Jun;41(6):745-52.
  12. Choi HS, Cho MC, Lee HG, et al. Indole-3-carbinol induces apoptosis through p53 and activation of caspase-8 pathway in lung cancer A549 cells. Food Chem Toxicol. 2010 Mar;48(3):883-90.
  13. Dashwood RH. Indole-3-carbinol: anticarcinogen or tumor promoter in brassica vegetables? Chem Biol Interact 1998;110:1-5.
  14. Yoshida M, Katashima S, Ando J, et al. Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N'-nitro-N-nitrosoguanidine, with induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism. Carcinogenesis. 2004 Nov;25(11):2257-64.
  15. Wong GY, et al. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl 1997;28-29:111-6.
  16. Hung WC, Chang HC. Indole-3-carbinol inhibits Sp1-induced matrix metalloproteinase-2 expression to attenuate migration and invasion of breast cancer cells. J Agric Food Chem. 2009 Jan 14;57(1):76-82.
  17. Meng Q, et al. Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. J Nutr 2000;130:2927-31.
  18. Bradlow HL, et al. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev 1994;3:591-5.
  19. Lyn-Cook BD, Mohammed SI, Davis C, et al. Gender differences in gemcitabine (Gemzar) efficacy in cancer cells: effect of indole-3-carbinol. Anticancer Res. 2010 Dec;30(12):4907-13.
  20. Rosen CA, et al. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg 1998;118:810-5.
  21. Jin L, et al. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res 1999;59:3991-7.
  22. Wang ML, Shih CK, Chang HP, Chen YH. Antiangiogenic activity of indole-3-carbinol in endothelial cells stimulated with activated macrophages. Food Chem. 2012 Sep 15;134(2):811-20.
  23. Qian X, Melkamu T, Upadhyaya P, Kassie F. Indole-3-carbinol inhibited tobacco smoke carcinogen-induced lung adenocarcinoma in A/J mice when administered during the post-initiation or progression phase of lung tumorigenesis. Cancer Lett. 2011 Dec 1;311(1):57-65.
  24. Wang H, Word BR, Lyn-Cook BD. Enhanced efficacy of gemcitabine by indole-3-carbinol in pancreatic cell lines: the role of human equilibrative nucleoside transporter 1. Anticancer Res. 2011 Oct;31(10):3171-80.
  25. Taylor-Harding B, Agadjanian H, Nassanian H, et al. Indole-3-carbinol synergistically sensitises ovarian cancer cells to bortezomib treatment. Br J Cancer. 2012 Jan 17;106(2):333-43.

Consumer Information

How It Works

Bottom Line: Indole 3-carbinol has cancer preventive effects. But it has not been shown to treat cancer in humans.

Indole-3-carbinol, also called I3C, is a compound found in vegetables such as broccoli, brussel sprouts, cabbage, cauliflower, and kale. It is known to stimulate detoxifying enzymes in the gut and liver, but it has come under more study lately for its potential anti-cancer properties. Animals that are fed a diet rich in I3C have a slower growth of their cancers. Laboratory studies show that it blocks estrogen activity by interfering with the estrogen receptor. This suggests that I3C might be useful in preventing or treating estrogen-sensitive cancers (such as breast and cervical cancers), possibly in addition to tamoxifen, but not enough studies have been done in humans to determine this. In addition, I3C can cause cell death in prostate cancer cells in the laboratory.
A few experiments in animals that showed that I3C increased the cancer-causing potential of certain environmental carcinogens, but this has not been confirmed in humans.

Purported Uses
  • To prevent cancer
    Laboratory and animal studies suggest that indole-3-carbinol may prevent estrogen-dependent cancers, but only one clinical trial has been performed, which showed that indole-3-carbinol can cause regression of cervical intraepithelial neoplasia (CIN), a condition that can lead to cervical cancer.
  • To detoxify the body
    Indole-3-carbinol stimulates detoxifying enzymes in the gut and liver, but this use has not been tested in clinical trials.
  • To treat viral infections
    No scientific evidence supports this use.
Research Evidence

Cervical cancer prevention:
A clinical trial was performed to study the ability of indole-3-carbinol (I3C) to treat cervical intraepithelial neoplasia (CIN), a pre-cancerous growth that can lead to cervical cancer. Thirty women enrolled in the study. They were randomly assigned to take (1) a placebo pill, (2) 200 mg/day of I3C, or (3) 400 mg/day of I3C for 12 weeks. At the end of the study, almost half of the women taking I3C had complete regression of their CIN, compared to none of the women who took placebo. Usually, CIN is surgically removed, so I3C may be a non-surgical option for women with this condition. More clinical trials will help establish this.

Do Not Take If
  • You are taking drugs that are substrates of Cytochrome P450 1A2 (I3-C may reduce the effectiveness of these drugs).
Side Effects
  • Skin rash
  • I3C may promote tumor growth in animals exposed to carcinogens. This effect has not been confirmed in humans.
E-mail your questions and comments to aboutherbs@mskcc.org.