Indole-3-Carbinol for Cancer Prevention
September 2000; Volume 3; 105-107
By Judith L. Balk, MD, FACOG
Fruit and vegetable consumption has been associated with a decreased risk of cancer.1 The cruciferous or Brassica vegetables recently have gained attention because several constituents may be cancer-protective.2 One of the main constituents, indole-3-carbinol (I3C), is being investigated for use as a chemopreventive agent. According to NIH, I3C usage is gaining popularity, with the market projected to grow 3,000% in two years.
Background
A review of epidemiological studies found that fruit and vegetable consumption was protective against cancer in 128 of 156 dietary studies, with six studies showing an increased risk of cancer.3 A dose-response relationship existed; after adjusting for potential confounders, individuals in the lowest quartile of fruit and vegetable intake had about twice the risk of cancer compared to those in the highest quartile. Another study found that breast cancer risk was reduced by 12% and 8%, respectively, for vegetable and fruit consumption, for each quintile increase in consumption.4 I3C is likely not to be the only protective constituent in cruciferous vegetables. Other components, such as fiber and sulphoraphanes, also may be cancer protective.5
Ongoing Trials
I3C was brought to the attention of the Chemical Selection Working Group at the National Cancer Institute because of its potential as a chemopreventive agent.6 Of 90 potential chemopreventive agents screened using biochemical chemoprevention endpoints, I3C was one of eight compounds that was positive in all six of the assays studied.7 It is being evaluated by the NCI’s Division of Cancer Prevention (DCP), and was nominated by the DCP for carcinogenicity, genotoxicity, and reproductive toxicity testing by the National Toxicology Program at the National Institute of Environmental Health Sciences.
Source and Identification
Indole-3-carbinol is a non-nutritive constituent of the cruciferous vegetable family, Brassica genus. Synonyms and trade names include 3-(hydroxymethyl) indole, I3C, indole-3-carbinol, 3-indolylcarbinol, and 3-indolylmeth-anol. Vegetables of the Brassica genus include cabbage, kale, broccoli, cauliflower, Brussels sprouts, kohlrabi, rape seed and oil, black and brown mustard greens, and root crops such as turnips and rutabagas.2
Pharmacology and Metabolism
Little is known about the pharmacology of I3C and its metabolites. No pharmacokinetic data in humans have been published. Data on the absorption, metabolism, and excretion of I3C are from in vitro and animal studies. I3C is present in cruciferous vegetables as the glucosinolate, which is cleaved by an enzyme in the plant whenever the plant is crushed or cooked to yield I3C. I3C is then converted by stomach acid to multiple oligomers and polyaromatic indolic compounds, including diindolylmethane (DIM) and indole (3,2,b)carbazole, also known as ICZ.
Excretion of metabolites occurs via urinary and fecal excretion. In a rat study, urinary and fecal excretion accounted for about 75% of the administered dosage, with fecal excretion representing 77% of the excretion.7 The multiple metabolites of I3C require reliable methods for quantification in serum or urine; to date, this has not been accomplished.
Mechanism of Action
Multiple mechanisms of action appear to exist for I3C’s chemopreventive action. The first is the effect on liver detoxification enzymes. I3C induces both phase 1 and phase 2 enzymes,8 so potentially it could increase9 or decrease10 the risk of cancer.
Briefly, the liver metabolizes toxic substances, such as carcinogens, in two phases. Phase 1 metabolism, typically via cytochrome P450 enzymes, renders the toxins more water soluble and easier to excrete. However, phase I products can be highly electrophilic and damaging to DNA. Phase 2 metabolism, via enzymes such as glutathione transferases, glucouronosyltransferases, and quinone reductases, makes the toxin even more readily excreted. The phase 1 system may be harmful by introducing hazardous substances whereas the phase 2 system is thought to be only detoxifying.5
Another mechanism of action involves metabolism of estradiol. Estradiol may be metabolized to 16a-hydroxy- estrone or to 2a-hydroxyestrone. The former is thought by many to be genotoxic, increasing the risk of breast and cervical cancer, whereas the latter is thought to be more benign and a weaker estrogen.11,12 Subjects consuming I3C have increased 2-hydroxylation of estrogen, which may be another mechanism that confers protection against hormone-dependent cancers.11
Other mechanisms have been demonstrated. I3C has also been shown to increase apoptosis and to cause cell cycle arrest in the breast cancer cell line MCF-7,13 and to function as an antioxidant.14 I3C has been shown to affect immune function in rats, enhancing delayed-type hypersensitivity but, at high doses, reducing natural killer cell activity.15 The authors postulate that the differential results in the immune assays may contribute to the diversity of findings in carcinogenicity studies.
Animal Studies
The majority of animal studies show inhibitory or protective effects of I3C on cancer, but some studies show evidence of an increased risk of cancer under certain experimental conditions. The discrepant findings are likely caused by differences in the initiator, exposure protocol, and species used.16 The timing of exposure to both the carcinogen and I3C seem to be important. Exposure to I3C prior to initiation with a carcinogen reduced the cancer rate, but when I3C was given after exposure to a carcinogen, I3C strongly enhanced the tumor incidence.17 The differential findings in the animal studies point to a need for more research to understand mechanisms of action.
Clinical Trials
Currently two clinical trials are studying I3C in breast cancer prevention.18 Preliminary results are not yet available, and other human data are limited at this time. I3C has been studied in human papillomavirus-mediated disease such as recurrent respiratory papillomatosis19 and cervical dysplasia.20 Rosen et al studied 18 children with recurrent respiratory papillomatosis.19 All were treated with I3C and were followed up for roughly 15 months. One third of patients had cessation of papilloma growth, one third had reduced growth, and one third had no clinical response from the I3C. No major complications or changes in the children’s growth curve were noted. The trial was not controlled, randomized, or masked. Bell et al presented an abstract of a randomized, placebo-controlled trial of 30 patients with biopsy-proved CIN II-III, with follow-up at 4, 8, and 12 weeks.20 No patients in the placebo group had regression of their dysplasia, whereas about 50% of patients in both dosages of the I3C group had complete regression. Human papillomavirus status did not correlate with response. No adverse effects were reported in this abstract.
Adverse Effects and Drug Interactions
I3C is being evaluated by the National Toxicology Program for evidence of adverse effects. Toxicity testing has resulted in inconsistent findings thus far, and no conclusion can be made currently. Toxicity analysis in one dose-ranging clinical trial revealed that two of 60 participants had isolated unexplained small increases in the liver enzyme SGPT, but it is unclear if these subjects were receiving placebo or I3C, or what the dosage of I3C was in these participants.21 A longer-term study found no changes in laboratory parameters.22 No drug interactions have been reported, but because of the induction of both phase 1 and 2 liver enzymes, drug interactions are possible.
Formulation and Dosage
I3C may be derived from cruciferous vegetables or it may be synthesized in the laboratory. I3C is sold at health food stores and pharmacies, either alone or in combination nutraceuticals.
A dose-ranging study suggested that a minimum effective dose of 300 mg/d was necessary for chemo- prevention of breast cancer.21 Other human trials have used 200-400 mg/d.19,20,22 Many supplements are available over the counter; the cost is roughly $30 per month. It would be difficult to reach a dietary intake of 300 mg/d. Western diets typically are low in I3C, whereas Japanese diets can range up to 112 mg/d.18 Concentrations of the I3C precursor glucosinolate in cruciferous vegetables are shown in Table 1.
| Table 1-Concentration of 3-indolylmethyl glucosinolates, including the precursor to I3C | |||
| Vegetable | Concentration (umol/ 100 g fresh weight) |
||
| Brussels sprouts | 327.8-469.4 | ||
| Collards | 67.2-165.3 | ||
| Kale | 44.2-102.3 | ||
| Broccoli | 42.2-71.7 | ||
| Kohlrabi | 27.7 | ||
| Cauliflower | 18.8-104.7 | ||
| Mustard greens | 4.2-12.2 | ||
| Source: Anonymous. Summary of data for chemical selection. Indole-3-Carbinol. National Institutes of Health: National Institute of Environmental Health Sciences; 1998. |
|||
Conclusion
Indole-3-carbinol has the potential to be an important agent for cancer prevention, especially hormonally dependent cancers. Epidemiologic, in vitro, animal, and human data support its use, but some in vitro and animal studies point to risks such as increased carcinogenesis. Future research must include a better understanding of risks and benefits, short- and long-term toxicologic studies, dosage, metabolism, and pharmocokinetics.
Recommendation
I3C may be a beneficial agent for chemoprevention, but more data are necessary prior to recommending this agent. Human exposure to a carcinogen may occur at any time, and the timing is typically unknown and uncertain. Therefore, one could not be sure that he or she is only ingesting I3C at a "safe" time. Because the issue of timing of carcinogen exposure relative to I3C exposure is not resolved, a recommendation for general use as a chemopreventive is premature. Furthermore, sulforaphanes, another component in cruciferous vegetables, may be cancer protective, so consuming isolated I3C may not be as good as consuming the vegetable itself. As Hippocrates long ago recommended, "Let food be thy medicine and medicine be thy food." Increasing consumption of cruciferous vegetables is a safer choice.
Dr. Balk is Assistant Professor of Obstetrics and Gynecology at the University of Pittsburgh.
References
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4. Trichopoulou A, et al. Consumption of olive oil and specific food groups in relation to breast cancer risk in Greece. J Natl Cancer Inst 1995;87:110-116.
5. Cronin J. Sulforaphane—Broccoli’s chemoprotective secret. Altern Complement Ther 2000;6:149-151.
6. Anonymous. Summary of data for chemical selection. Indole-3-Carbinol. National Institutes of Health: National Institute of Environmental Health Sciences; 1998.
7. Anonymous. Clinical development plan: Indole-3-carbinol. J Cell Biochem Suppl 1996;26:127-136.
8. Chen I, et al. Indole-3-carbinol and diindolyomethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells. Biochem Pharmacol 1996;51:1069-1076.
9. Pence B, et al. Multiple dietary factors in the enhancement of dimethylhydrazine carcinogenesis: Main effect of indole-3-carbinol. J Natl Cancer Inst 1986;77: 269-276.
10. Fahey JW, et al. Broccoli sprouts: An exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci USA 1997;94:10367-10372.
11. Michnovicz JJ. Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. Int J Obes Relat Metab Disord 1998;22:227-229.
12. Yuan F, et al. Anti-estrogenic activities of indole-3-carbinol in cervical cells: Implication for prevention of cervical cancer. Anticancer Res 1999;19:1673-1680.
13. Bradlow HL, et al. Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent. Ann NY Acad Sci 1999;889:204-213.
14. Shertzer HG, et al. Intervention in free radical mediated hepatotoxicity and lipid peroxidation by indole-3-carbinol. Biochem Pharmacol 1988;37:333-338.
15. Exon J, South E. Dietary indole-3-carbinol alters immune functions in rats. J Toxicol Environ Health, Part A 2000;59:271-279.
16. Dashwood RH. Indole-3-carbinol: Anticarcinogen or tumor promoter in brassica vegetables? Chem Biol Interact 1998;110:1-5.
17. Bailey GS, et al. Enhancement of carcinogenesis by the natural anticarcinogen indole-3-carbinol. J Natl Cancer Inst 1987;78:931-934.
18. Anonymous. Background Information: Indole-3-Carbinol. National Institutes of Health: National Institute of Environmental Health Sciences; 2000.
19. Rosen CA, et al. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg 1998;118: 810-815.
20. Bell MC, et al. Placebo-controlled trial of indole-3-carbinol in the treatment of cervical dysplasia. Presented at: 30th Annual Meeting of the Society of Gynecologic Oncologists, March 20-24, 1999; San Francisco, CA.
21. Wong G, et al. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppls 1997;28/29:111-116.
22. Bradlow HL, et al. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev 1994;3:591-595.
September 2000; Volume 3; 105-107
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