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From The April 2001 Issue of Nutrition Science News
I3C and DIM: Keys to Cancer Prevention?
Thomas Incledon, R.D.
Scientists know that higher consumption of cruciferous vegetables such as broccoli, cabbage, and cauliflower is associated with a lower incidence of various cancers.1,2 It seems certain compounds within these foods decrease the effects of cancer-causing chemicals. 3 One such compound is glucobrassicin. After a person eats broccoli, for example, glucobrassicin is metabolized into several compounds in the gastrointestinal tract, including indole-3-carbinol (I3C).3 In the presence of acid, as exists in the stomach, I3C is broken down into various by-products, including 3,3'-diindolylmethane (DIM). 3 The significance of this metabolic minutia is that studies indicate one of I3C's metabolites, perhaps DIM, may have chemopreventive properties.
Recent research reveals promising results regarding I3C and DIM, two compounds isolated from cruciferous vegetables with potential as anticancer agents.
To understand how I3C and DIM affect the human body and cancer risk requires a look at estrogen metabolism. Estrogens are hormones necessary for various functions including bone maintenance and female sexual development. However, we know that women with higher circulating estrogen levels have an increased breast-cancer risk. The potent estrogen estradiol is converted into less potent estrogens, or "daughter compounds."
Estradiol and estrone interconvert; that is, they can easily change back and forth. The body has to get rid of excess estrogen and has a sophisticated detoxification system to do so. For example, the liver can then metabolize estrone and estradiol into 2-hydroxyestrone and 2-hydroxyestradiol by hydroxylating the second carbon. These steroid daughter compounds can in turn be converted into 2-methoxy-estrone and 2-methoxyestrodial, which are called catechol estrogens. These weak estrogens can act as anti-estrogens—that is, they can decrease other estrogen activity in the body.4-6
What further complicates this situation is that estrone and estradiol can be converted to other daughter estrogens through other metabolic pathways, sort of like dueling pathways. The pathway on the right in Figure 1 shows that estrone can be hydroxylated at the 16th carbon position to form 16-alpha-hydroxy-estrone. This steroid can then be converted into estriol. Increased 16-alpha-hydroxyestrone production has been linked to an increase in breast cancer.7,8 Based on estrogen metabolism's influence on breast-cancer risk, researchers speculate that reducing hydroxylation of estrone's 16th carbon and increasing hydroxylation of the second carbon would be a wise, protective measure.
Testing The Theory
Researchers have examined the effects of I3C on cell and animal cancer models.9-12 Collectively, the results are generally positive. This preliminary work stimulated interest at the National Cancer Institute in Bethesda, Md., which developed a plan to systematically study I3C's therapeutic potential as a chemopreventive agent.9,13 In a randomized human trial at the Institute for Hormone Research in New York City, 60 female patients took 400 mg/day I3C for three months. The regimen increased production of 2-hydroxyestrone, thus further supporting the theory that I3C may function as a preventive agent against breast cancer.14
Three years later, researchers at Strang Cancer Prevention Center in New York City studied 57 women at risk for breast cancer in a double-blind, placebo-controlled dose-ranging study using 0, 50, 100, 200, 300, and 400 mg I3C/day.15 The minimum effective dose to increase the ratio of 2-hydroxyestrone to 16-alpha-hydroxyestrone was 300 mg/day. Toxicity analysis indicated no abnormalities in clinical chemistries or complete blood counts, except for two subjects who experienced unexplained slight, nonsignificant increases in a liver enzyme used to assess liver function. The dosage level was not stated.
In addition to breast cancer, I3C has also been studied for therapeutic effects in other clinical conditions, including recurrent respiratory papillomatosis (RRP), a rare disease characterized by benign growths in the mucosa from the mouth to the lungs. The suspected etiologic agent of RRP has been human papilloma virus (HPV) types 6 and 11.16 Researchers at the University of Pittsburgh Medical Center studied 18 children and adults with RRP. Children were dosed based upon their body weight, while adults took 200 mg I3C twice daily for at least eight months and a mean follow-up at 14.6 months. Six out of 18 subjects (33 percent) had complete papilloma cessation, six others had reduced papilloma growth rates, and the remaining six saw no change in papilloma growth rate.17 These findings warrant further investigation of I3C for RRP treatment.
Another disease potentially induced by HPV is cervical cancer. Precancerous lesions of the cervix can be treated with chemopreventive agents to deter cervical and vaginal cancer.18 In a placebo-controlled human trial, 200 mg/day I3C resulted in complete regression of cervical precancerous growth in four of eight patients, and 400 mg/day resulted in complete regression in four of nine patients. In the placebo group, no patients had complete regression.19
Taken together, results from the animal and human studies seem to indicate I3C has therapeutic potential against HPV-induced growths in the cervix, vagina, and respiratory tract. No studies have yet shown I3C or any of its metabolites to prevent breast cancer in humans, but there seems to be an association between breast-cancer risk and depressed 2-hydroxyestrone levels, elevated 16-alpha-hydroxyestrone levels, or a lower 2/16 ratio. As interesting as the data are thus far, many questions still need to be answered.
The Claims Game
Numerous claims have touted I3C and DIM as cancer-fighters and muscle-builders. Take care when evaluating claims that apply results from a study on one population (such as obese men and women) to other groups (such as the nonobese or athletes). Although increasing the ratio of 2-hydroxy-estrone to 16-alpha-hydroxyestrone appears to be a sound strategy for reducing the risk for various cancers, it may not work for everyone. For example, body composition influences the C2-hydroxylation process of the estrogen metabolite estrone in humans.20,21 The hydroxylation rate of the second carbon in lean people is high; increasing it further may be difficult in this group and may not yield benefit.
Most of the research thus far has focused on I3C, a phytonutrient converted by stomach acid to DIM, indolylcarbazole, and other metabolites.22,23 Because I3C requires the presence of acid, it is effective only in oral doses and has no effect when injected.24 A 350-500 mg dose of I3C is roughly equal to 300-500 mg of raw cabbage or brussels sprouts or about 3 cups of broccoli, so a study comparing the relative effectiveness of whole foods vs. isolated agents would be useful for guiding health care recommendations.
Future research should also compare the effects of DIM against I3C, especially in populations with compromised gastrointestinal function, which would minimize conversion of I3C to DIM.
Other exciting research opportunities include combining I3C or DIM with other breast-cancer treatments. Cell studies indicate the combination of I3C and tamoxifen can arrest breast cancer cell growth.25
Don't be seduced by the claims. Crucifers certainly hold promise, but so far all we know is that I3C, at doses of 200-400 mg per day, may have therapeutic potential as a chemopreventive agent.
Thomas Incledon, R.D., is vice president of Human Performance Specialists in Plantation, Fla.
References
1. Graham S, et al. Alimentary factors in the epidemiology of gastric cancer. Cancer 1972;30(4):927-38.
2. Young TB, Wolf DA. Case-control study of proximal and distal colon cancer and diet in Wisconsin. Int J Cancer 1988;42(2):167-75.
3. McDanell R, et al. Chemical and biological properties of indole glucosinolates (glucobrassicins): a review. Food Chem Toxicol 1988;26(1):59-70.
4. Martucci CP, Fishman J. Impact of continuously administered catechol estrogens on uterine growth and luteinizing hormone secretion. Endocrinology 1979;105(6):1288-92.
5. Schneider J, et al. Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J Biol Chem 1984;259(8):4840-5.
6. Vandewalle B, Lefebvre J. Opposite effects of estrogen and catecholestrogen on hormone-sensitive breast cancer cell growth and differentiation. Molecular Cellular Endocrinol;1989:61(2):239-46.
7. Fishman J, et al. Increased estrogen-16 alpha-hydroxylase activity in women with breast and endometrial cancer. J Steroid Biochem 1984;20(4B):1077-81.
8. Swaneck GE, Fishman J. Covalent binding of the endogenous estrogen 16 alpha-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization. Proc Natl Acad Scien USA 1988;85(21):7831-5.
9. Kelloff GJ, et al. Strategy and planning for chemopreventive drug development: clinical development plans II. J Cellular Biochem Suppl 1996;26:54-71.
10. Kelloff GJ, et al. New agents for cancer chemoprevention. J Cellular Biochem Suppl 1996;26:1-28.
11. Kelloff GJ, et al. Progress in cancer chemoprevention. Ann NY Acad Scien 1999;889:1-13.
12. Kelloff GJ, et al. Progress in cancer chemoprevention: development of diet-derived chemopreventive agents. J Nutr 2000;130(2S Suppl):467S-71S.
13. Anonymous. Clinical development plan: indole-3-carbinol. J Cell Biochem Supplement 1996;26:127-36.
14. Bradlow HL, et al. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev 1994. 3(7): p. 591-5.
15. Wong GY, et al. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Supplement 1997;29:111-6.
16. Coll DA, et al. Treatment of recurrent respiratory papillomatosis with indole-3-carbinol. Am J Otolaryngol 1997.18(4):283-5.
17. Rosen CA, et al. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg 1998;118(6):810-5.
18. Jin L, et al. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res 1999;59(16):3991-7.
19. Snow RR, et al. Estrogen 2-hydroxylase oxidation and menstrual function among elite oarswomen. J Clin Endocrinol Metab 1991:69:369-76.
20. Schneider J, et al. Effects of obesity on estradiol metabolism: decreased formation of nonuterotropic metabolites. J Clin Endocrin Metab 1983:56(5):973-8.
21. Bjeldanes LF, et al. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc Nat Acad Scien USA 1991;88(21):9543-7.
22. Jellinck PH, et al. Ah receptor binding properties of indole carbinols and induction of hepatic estradiol hydroxylation. Biochem Pharmacol 1993;45(5):1129-36.
23. Bradfield CA, Bjeldanes LF. Structure-activity relationships of dietary indoles: a proposed mechanism of action as modifiers of xenobiotic metabolism. J Toxicol Environ Health 1987;21(3):311-23.
24. 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(6):1244-51.
25. Seeger H, et al. The inhibitory effect of endogenous estrogen metabolites on copper- mediated in vitro oxidation of LDL. Int J Clin Pharmacol Therapeut 1998;36(7):383-5.
26. Seeger H, et al. Effect of estradiol metabolites on the susceptibility of low-density lipoprotein to oxidation. Life Sciences 1997;61(9):865-8.
27. Seeger H, et al. Thye antiproliferative effects of 17beta-estradiol metabolites on human coronary artery smooth muscle cells. Med Science Res 1998;26:481-2.
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