Indole-3-Carbinol

What Is It?

Indole-3-carbinol is a plant hormone naturally found in cruciferous vegetables, and it is derived from a substance known as glucosinate glucobrassicin$^{1}$. When these plant tissues are damaged through the process of chewing or cooking, an enzyme called myrosinase is released and subsequently causes the breakdown of glucosinolate glucobrassicin into indole-3-carbinol$^{1}$. Recently, this plant hormone has started to receive significant scientific scrutiny as it has been discovered to exhibit anticarcinogenic and anti-inflammatory properties through a variety of pathways.

What Are Its Other Names?

Indole-3-carbinol is commonly abbreviated to I3C, but it is also known as 3-hydroxymethyl indole, or indole-3-methanol$^{2}$. The IUPAC name for indole-3-carbinol is 1H-indol-3-ylmethanol$^{3}$.

Indoles vs Indole-3-carbinol

It is important to note that while indoles and indole-3-carbinol may demonstrate some structural resemblances, they are not the same compound. Indoles are an organic compound typically produced by bacteria, and they are used as flavouring agents$^{4}$. Many substances contain an indole structural moiety, for example indole alkaloids (found in ‘magic mushrooms’ and the poison strychnine) and indole-3-carbinol$^{5}$. Thus, it is important to be aware of this distinction so as to avoid mistaking indole-3-carbinol for indoles or other indole-based compounds, some of which may be harmful.

What Foods Have It?

What Are Its Main Benefits?

Improvement in Precancerous Conditions Indole-3-carbinol has shown promising results in the improvement of precancerous conditions caused by human papillomavirus (HPV) infection. Certain strains of HPV can lead to the development of cervical intraepithelial neoplasia (abnormal growth on the cervix), vulvar intraepithelial neoplasia (lesion on the surface of the vulva) and recurrent respiratory papillomatosis (benign tumour found in the larynx, trachea, bronchi, and lungs)$^{7,8,9}$. If these benign growths are left untreated, they have the capacity to develop into malignant tumours and lead to cancer. A number of studies reported that indole-3-carbinol supplementation resulted in the regression or reduced recurrence of these tumours$^{10,11,12}$. Promoting Hormonal Balance Indole-3-carbinol has been linked to promoting the balance of estrogen levels which is especially beneficial to women. It accomplishes this by regulating the expression of specific CYP450 enzymes (enzymes involved in the metabolism and elimination of hormones, drugs, and carcinogens) which consequently downregulates estrogen production$^{9}$. Maintaining this balance is significant because prolonged exposure to high levels of estrogen can increase an individual’s risk of endometriosis, endometrial hyperplasia (abnormal thickening of uterine lining), and estrogen-induced cancers (breast, ovarian, and endometrial)$^{13}$. Improvement in Inflammatory Conditions Beyond cancer, indole-3-carbinol is also beneficial for patients with chronic diseases caused by inflammation, such as cardiovascular disease, rheumatoid arthritis, and ischemic stroke$^{14,15,16}$. Several studies have demonstrated that this plant hormone can attenuate the inflammatory immune response by regulating specific cell signalling pathways and by reducing the release of proinflammatory cytokines$^{14,17}$.

What Are Its Main Drawbacks?

Possible Drug Interactions The main drawback of indole-3-carbinol is its ability to interact with CYP450 enzymes, primarily CYP1A2 enzymes$^{18}$. CYP1A2 accounts for 13-15% of CYP enzymes in the liver and is responsible for the metabolism of many clinical drugs like caffeine, propranolol, and clozapine$^{19}$. Thus, altering the expression of CYP1A2 could affect the target serum drug concentration and lead to adverse drug interactions in the body. Potential Adverse Reactions In one study, it was reported that indole-3-carbinol supplementation led to the development of a skin rash in one patient with systemic lupus erythematosus$^{20}$. A separate study involving 24 healthy women found that indole-3-carbinol at high doses (>800 mg) caused nausea and vomiting$^{21}$. However, these gastrointestinal symptoms improved once the dosage was adjusted, and these women ultimately recovered with no long-term effects. Another study involving patients with respiratory papillomatosis highlighted that indole-3-carbinol supplementation resulted in disequilibrium (a feeling of unsteadiness and spatial disorientation)$^{20,22}$. It is essential to note that in two of the three cases discussed, adverse reactions were reported in patients with pre-existing medical conditions which may have contributed to their reaction. Overall, it is important to consult with your healthcare provider to determine if indole-3-carbinol supplements are the right course of action for your condition, as well as for determining the appropriate dosage that minimizes the risk of any potential harmful side effects.

How Does It Work?

Indole-3-carbinol exhibits its anticancer effects through the following mechanisms: regulating estrogen levels to prevent DNA damage, inducing cell cycle arrest to suppress tumour formation, and inhibiting cell migration and angiogenesis.

What Are Its Mechanisms of Action?

1. Regulating Estrogen Levels: Indole-3-carbinol has been shown to control estrogen levels through a variety of mechanisms. Firstly, it can decrease the expression of CYP19 aromatase (an enzyme that converts androgens to estrogen) and thus hinder estrogen synthesis$^{23,24}$. Alternatively, indole-3-carbinol can also bind to and activate aryl hydrocarbon receptors (AhR), causing an increased production of CYP1A1 and CYP1A2 enzymes. These enzymes will then initiate the breakdown of estrogen into a metabolite that is non-toxic and readily eliminated by the body, thus reducing the circulating levels of this hormone$^{25}$. High levels of estrogen can contribute to cancer development because available CYP1B1 enzymes can transform circulating estrogen to a 4-hydroxy metabolite and lead to DNA damage$^{26}$. Therefore, it is critical to maintain this fine balance of estrogen in order to prevent the development of estrogen-dependent cancers.
2. Induction of Cell Cycle Arrest: In addition to modulating estrogen levels, indole-3-carbinol can also inhibit the growth of tumour cells by inducing cell cycle arrest. This is attributed to its ability to inhibit the expression of G1 cyclin dependent kinase (CDK6) (a protein that drives cell cycle progression) as well as enhance the production of G1 cell cycle inhibitors$^{25,27,28}$. This prevents a cell from progressing to the next phase of the cell cycle, thus it consequently enters a non-dividing state known as G0$^{25,27,28}$. Ultimately, this results in a decrease in cellular division and a consequent suppression of tumour proliferation$^{29}$.
3. Inhibition of Cell Migration: One study conducted on breast cancer cells demonstrated that indole-3-carbinol can also hamper tumour metastasis by inhibiting the migration of these cancer cells. It reported that indole-3-carbinol can reduce the levels of specific proteins and enzymes associated with cell migration, specifically vimentin, focal adhesion kinase, and matrix metalloproteins$^{29}$.
4. Inhibition of Angiogenesis: Angiogenesis is the process by which tumours form new blood vessels to develop a steady blood supply to obtain essential nutrients and oxygen in order to survive and proliferate$^{30}$. In one study, it was found that indole-3-carbinol disrupted the secretion of molecules that promote angiogenesis, namely, nitric oxide (NO), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6)$^{31}$. In the absence of a stable blood supply, the tumour cells are less likely to spread.

What Are Typical Doses and Durations?

Dosage

Clinical studies that investigate the anticarcinogenic effects of indole-3-carbinol have used doses ranging from 50 mg/day to 1,200 mg/day$^{21,32,33,34}$. Indole-3-carbinol was typically administered as an oral capsule taken once daily, or multiple capsules taken throughout the day. For example, two capsules of 200 mg taken at two regular intervals each day for a 400 mg dose. These studies found that the maximum tolerated dose of indole-3-carbinol is 400 mg/day, and that doses beyond this threshold may result in adverse reactions$^{21}$. Furthermore, it was also discovered that indole-3-carbinol is most effective at doses ranging from 300 mg/day to 400 mg/day$^{33,34}$. Duration Most clinical studies investigating the anticancer effects of indole-3-carbinol have typically lasted over a period of several weeks (4 weeks to 12 weeks), with only one study lasting up to 3 months$^{21,33,34}$. However, long-term studies examining the effects of indole-3-carbinol on cancer are relatively limited. Although these clinical studies demonstrate promising results for indole-3-carbinol supplementation, it is important to note that these findings are based on preliminary data. There is currently no conclusive evidence to support the use of indole-3-carbinol for cancer prevention. Thus, it is recommended to consult your healthcare provider before starting any dietary regimen.

Summary of Data

A total of six randomised controlled trials were identified from PubMed that investigated indole-3-carbinol as a means of preventing or treating cancer. A summary of the results for each cancer type is as follows:

📄 Detailed Indole-3-carbinol human clinical trial study notes analyzed by Anticancer.ca

References

1. Katz, E., Nisani, S. & Chamovitz, D. A. Indole-3-carbinol: A plant hormone combatting cancer. F1000Research 7,689 (2018).
2. NCI Drug Dictionary. National Cancer Institute Available at: https://www.cancer.gov/publications/dictionaries/cancer-drug/def/indole-3-carbinol. (Accessed: 20th June 2023)
3. Indole-3-carbinol. National Center for Biotechnology Information. PubChem Compound Database Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Indole-3-carbinol. (Accessed: 20th June 2023)
4. Indole. National Center for Biotechnology Information. PubChem Compound Database Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Indole. (Accessed: 16th July 2023)
5. Indole alkaloid. Encyclopædia Britannica Available at: https://www.britannica.com/science/indole-alkaloid. (Accessed: 16th July 2023)
6. McNaughton, S. A. & Marks, G. C. Development of a food composition database for the estimation of dietary intakes of glucosinolates, the biologically active constituents of cruciferous vegetables. British Journal of Nutrition90, 687–697 (2003).
7. Cervical Intraepithelial Neoplasia. National Cancer Institute Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cervical-intraepithelial-neoplasia. (Accessed: 28th June 2023)
8. Lee, S. Precancerous conditions of the vulva. Canadian Cancer Society Available at: https://cancer.ca/en/cancer-information/cancer-types/vulvar/what-is-vulvar-cancer/precancerous-conditions. (Accessed: 28th June 2023)
9. Higdon, J., Drake, V. J., Delage, B. & Williams, D. E. Indole-3-carbinol. Linus Pauling Institute (2023). Available at: https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/indole-3-carbinol#HPV-related-diseases-treatment. (Accessed: 28th June 2023)
10. Naik, R. et al. A randomized phase II trial of indole-3-carbinol in the treatment of vulvar intraepithelial neoplasia.International Journal of Gynecological Cancer 16, 786–790 (2006).
11. Bell, M. C. et al. Placebo-controlled trial of indole-3-carbinol in the treatment of cin. Gynecologic Oncology 78,123–129 (2000).
12. Rosen, C. A. & Bryson, P. C. Indole-3-carbinol for recurrent respiratory papillomatosis: Long-term results. Journal of Voice 18, 248–253 (2004).
13. Romm, A. High estrogen: What it means and what you can do. Aviva Romm, MD (2023). Available at: https://avivaromm.com/high-estrogen/. (Accessed: 28th June 2023)
14. Chichai, A. S., Popova, T. N., Kryl’skii, E. D., Oleinik, S. A. & Razuvaev, G. A. Indole-3-carbinol mitigates oxidative stress and inhibits inflammation in rat cerebral ischemia/reperfusion model. Biochimie 213, 1–11 (2023).
15. Hasan, H., Ismail, H., El-Orfali, Y. & Khawaja, G. Therapeutic benefits of indole-3-carbinol in adjuvant-induced arthritis and its protective effect against methotrexate induced-hepatic toxicity. BMC Complementary and Alternative Medicine 18, 337 (2018).
16. Prado, N. J. et al. Anti-inflammatory, antioxidant, antihypertensive, and antiarrhythmic effect of indole-3-carbinol, a phytochemical derived from cruciferous vegetables. Heliyon 8, (2022).
17. Jiang, J. et al. Indole-3-carbinol inhibits LPS-induced inflammatory response by blocking TRIF-dependent signaling pathway in macrophages. Food and Chemical Toxicology 57, 256–261 (2013).
18. Leibelt, D. A., Hestrom, O. R., Fischer, K. A., Pereira, C. B. & Williams, D. E. Evaluation of chronic dietary exposure to indole-3-carbinol and absorption-enhanced 3,3’-diindolylmethane in Sprague-Dawley Rats. Toxicological Sciences 74, 10–21 (2003).
19. Guo, J. et al. Metabolism and mechanism of human cytochrome P450 enzyme 1A2. Current Drug Metabolism 22,40–49 (2021).
20. Minich, D. M. & Bland, J. S. A review of the clinical efficacy and safety of cruciferous vegetable phytochemicals. Nutrition Reviews 65, 259–267 (2008).
21. Reed, G. A. et al. Single-dose and multiple-dose administration of indole-3-carbinol to women: Pharmacokinetics based on 3,3′-diindolylmethane. Cancer Epidemiology, Biomarkers & Prevention 15, 2477–2481 (2006).
22. Dizziness, Disequilibrium & balance disorders: Pacific Eye & Ear Center. Pacific Eye & Ear (2020). Available at: https://www.pacificneuroscienceinstitute.org/eye-ent/hearing/conditions/balance-disturbance/. (Accessed: 29th June 2023)
23. CYP19A1 gene: Medlineplus genetics. MedlinePlus (2014). Available at: https://medlineplus.gov/genetics/gene/cyp19a1/. (Accessed: 29th June 2023)
24. Licznerska, B. E., Szaefer, H., Murias, M., Bartoszek, A. & Baer-Dubowska, W. Modulation of CYP19 expression by cabbage juices and their active components: Indole-3-carbinol and 3,3′-diindolylmethene in human breast epithelial cell lines. European Journal of Nutrition 52, 1483–1492 (2012).
25. Fan, S., Meng, Q., Auborn, K., Carter, T. & Rosen, E. M. BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and Genistein in breast and prostate cancer cells. British Journal of Cancer 94,407–426 (2006).
26. Cirillo, F. et al. GPER is involved in the regulation of the estrogen-metabolizing CYP1B1 enzyme in breast cancer. Oncotarget 8, 106608–106624 (2017).
27. CDK6 cyclin dependent kinase 6 [homo sapiens (human)] - gene - NCBI. National Center for Biotechnology Information (2023). Available at: https://www.ncbi.nlm.nih.gov/gene/1021. (Accessed: 1st July 2023)
28. Ho, J.-N., JUN, W., CHOUE, R. & LEE, J. I3c and ICZ inhibit migration by suppressing the EMT process and FAK expression in breast cancer cells. Molecular Medicine Reports 7, 384–388 (2012).
29. Zhang, L. et al. Cdk6-PI3K signaling axis is an efficient target for attenuating ABCB1/P-GP mediated multi-drug resistance (MDR) in cancer cells. Molecular Cancer 21, (2022).
30. Angiogenesis inhibitors. National Cancer Institute (2018). Available at: https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet. (Accessed: 1st July 2023)
31. Wang, M.-L., Shih, C.-K., Chang, H.-P. & Chen, Y.-H. Antiangiogenic activity of indole-3-carbinol in endothelial cells stimulated with activated macrophages. Food Chemistry 134, 811–820 (2012).
32. Bradlow, H. L. et al. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (1994). Available at: https://pubmed.ncbi.nlm.nih.gov/7827590/. (Accessed: 18th July 2023)
33. Reed, G. A. et al. A phase I study of indole-3-carbinol in women: Tolerability and Effects. Cancer Epidemiology, Biomarkers & Prevention 14, 1953–1960 (2005).
34. Wong, G. Y. C. et al. Dose-ranging study of indole-3-carbinol for breast cancer prevention. Journal of Cellular Biochemistry 67, 111–116 (1997).
35. Bradlow, H. L. et al. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev 3, 591-595 (1994).

About This Article

Disclaimer

The content on Anticancer.ca is intended for educational and informational purposes only and does not serve as a substitute for professional medical advice or services. Consult a licensed physician for personalized medical advice or questions about your health. Do not disregard professional advice or delay seeking help based on information found on our website. In case of a medical emergency, call 911 or visit the nearest emergency room immediately.

Anticancer.ca strives to provide accurate and reliable information but cannot guarantee its error-free or comprehensive nature. We are not responsible for the quality or endorsement of information, services, products, treatments, or therapies provided by third parties mentioned on our website. Always consult a qualified healthcare professional before making medical decisions.

• Indole-3-Carbinol
• What Is It?
• What Are Its Other Names?
• What Foods Have It?
• What Are Its Main Benefits?
• What Are Its Main Drawbacks?
• How Does It Work?
• What Are Its Mechanisms of Action?
• What Are Typical Doses and Durations?
• Summary of Data
• References
• About This Article
• Disclaimer