Scientific Name(s): Brassica oleracea L. var. botrytis L. Family: Brassicaceae (mustard)
Common Name(s): Broccoli , calabrese , chou broccoli , common broccoli , cruciferous vegetable , sprouting broccoli , indole-3-carbinol (I3C) , di-indolylmethane (DIM) , BioResponse , Indolplex
Cruciferous vegetables, including broccoli, are being investigated for a potential role in the prevention and treatment of cancer, but no recommendations can be made. Broccoli is a useful natural source of selenium.
Broccoli 500 g daily and broccoli sprouts 50 g daily have been used in clinical trials. Preparation methods affect bioavailability of active chemical compounds and relevant endogenous enzymes.
Information regarding safety and efficacy in pregnancy and lactation is lacking.
Reports of clinically important interactions are lacking. High consumption of broccoli may interfere with international normalized ratio (INR) values, antagonizing the effect of warfarin, but bioavailability of vitamin K is poor.
Few reported in clinical trials.
Effects on thyroid function have been suggested. Tumor-promoting effects of DIM have been shown in some animal models, especially at higher dosages.
The Brassica L. (mustard) genus includes cabbages, turnips, and pak choi; broccoli was derived from a species of wild cabbage. With extensive cultivation and selection, the B. oleracea species has become diverse, with many different varieties divided into several groups, including brussels sprouts (var. gemmifera ), kohlrabi (var. gongylodes ), sprouting broccoli (var. italica ), and tronchuda cabbage (var. costata ). Common broccoli (var. botrytis ) has been developed to have a dense, central flowering head (10 to 20 cm) on a thick stem, with the head surrounded by petiolate leaves. Both green and purple broccoli varieties exist. Sprouting broccoli, also known as Italian or asparagus broccoli (var. italica ), has loose, leafy stems and edible flower shoots, with no central head. Broccoli is a cool weather crop and is grown mostly in California and Arizona in the United States. 1
Broccoli is thought to have been domesticated in ancient Rome from wild cabbage, and it was introduced to the United States by Italian immigrants in the early 20th century. Usually boiled or steamed, broccoli is popular as a quick frozen vegetable, and it is recognized as a functional food, having health benefits beyond its nutritive value. 2 , 3 Extracts have been used in skin disorders and to treat warts. 2
Raw, green broccoli is a source of multiple vitamins and minerals, including calcium, magnesium, potassium, iron, zinc, and selenium, as well as carotene, thiamine, riboflavin, niacin, folate, and vitamins C and K; however, content varies widely and the bioavailability of compounds may be low. Flavonoids (eg, quercetin, kaempferol), hydroxycinnamoyl compounds, and glucosinolates (primarily glucoraphanin and glucobrassican) have been described. Broccoli sprouts are consumed for their higher glucosinolate content. The glucosinolates give the species its characteristic taste and are influenced by cultivation methods. 2 , 3 , 4
Glucosinolates have been extensively studied; approximately 120 compounds have been identified. The compounds are inactive after ingestion until hydrolyzed by the myrosinase enzyme endogenous to the plant. The respective isothiocyanates (particularly sulforaphane, I3C, and 3,3-DIM) are excreted via the urine as the corresponding mercapturic acids. 2 , 4 , 5 , 6 Levels of glucosinolates are affected by food processing; chopping broccoli increases the activity of myrosinase, while pulping broccoli in a blender will result in complete breakdown by autolysis. Cooking decreases glucosinolate levels up to 60%, depending on the method employed, and deactivates endogenous myrosinase, leaving the bacterial enzymes in the distal gut responsible for hydrolysis. 2 , 7 , 8
Uses and PharmacologyCancer
Multiple mechanisms of action for broccoli and its constituents (especially sulforaphane, DIM, and I3C) have been proposed based largely on cell culture studies. Mechanisms include the induction of phase 1, 2, and 3 enzyme and transporter systems, phase 2 detoxification, inhibition of histone deacetylation, cell cycle arrest, apoptosis, and the inhibition of cell growth. 4 , 5 , 6 , 7 , 9 , 10 , 11 , 12 , 13
Of particular interest is the effect of I3C and DIM on estrogen metabolism. 14 , 15 , 16 Both compounds appear to affect the concentrations of 2-, 4-, and 16-hydroxyestrone (-OHE) estrogen metabolites. Studies have shown that I3C and DIM are capable of increasing levels of 2-OHE and decreasing 16-OHE, suggesting a decreased cancer risk. Changes in the physiological levels of 4-OHE are considered to be too small to be of relevance; however, the metabolite is considered potentially mutagenic. 14 , 15 , 17 , 18 , 19 Antiandrogenic properties have also been demonstrated for DIM. 20
Published reviews of epidemiological data investigating the role of broccoli in cancer prevention have not all demonstrated a positive protective effect, but harm was not demonstrated. 7 , 21 No association was found for flavonoid-rich foods or broccoli with the incidence of total and site-specific cancers among middle-aged and older women in the Women's Health Study. 22 Likewise, no association was demonstrated for flavonoids and the incidence of ovarian cancer; however, an inverse association with broccoli intake, attributed to kaempferol, was found. 23 In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, vegetable and fruit consumption was not related to prostate cancer risk overall, but broccoli appeared to be protective for risk of aggressive, extraprostatic prostate cancer. 24 The European Prospective Investigation into Cancer and Nutrition study found no association between cruciferous vegetable consumption and the risk of prostate cancer. 25 In the Health Professionals Follow-Up Study, 5 or more servings of broccoli per week showed a protective effect for bladder cancer, while 2 further reviews showed 3 to 5 servings per week to be protective for prostate cancer. 7 A review of epidemiological data for prostate cancer found modest support for a protective effect of Brassica vegetables, with 4 of 12 studies demonstrating statistically significant protection but noting bias to be a particular problem. 21Animal studies
Broccoli, sulforaphane, and various glucosinolates/isothiocyanates have been used in experiments in mice and rats with induced prostate, small intestine, skin, and mammary cancers. 7 , 14 , 15 , 26 Limited animal studies have shown an increase in carcinogenic activity, such as increased liver cancer in trout fed DIM, and apoptosis in splenic cells in mice. 15 , 27 , 28Clinical studies
Prospective clinical trials are limited. A clinical phase 1 study has been undertaken to research the safety, tolerance, and metabolism of broccoli sprouts. 29 Variations in human genotypes have been suggested to influence response to the protective effects of cruciferous vegetables. 30 , 31 Two trials evaluated the effect of broccoli on biomarkers for breast cancer and found a protective effect suggesting a protective role in hormone-dependent cancers. 32 , 33 Results from a trial evaluating the effect of broccoli on breast cancer recurrence among breast cancer survivors are not available. 34 A 12-month trial of a broccoli-rich diet showed a protective effect for prostate cancer biomarkers. 35
Although the majority of clinical studies have investigated the effect of I3C in cancer, especially in breast and prostate cancers, I3C is rapidly transformed into DIM in the stomach and is considered by some researchers to be a prodrug of DIM. Poor oral bioavailability of naturally derived DIM has led to development of synthetic analogs. 18 , 36 At least 8 registered clinical trials are being conducted using DIM, and phase 1 dose escalation and safety trials have been conducted. 17 , 18 , 37 , 38 , 39 , 40 Preliminary results from clinical trials are encouraging, although not all studies have produced positive findings. 14 , 15 , 41Other effects
Broccoli 500 g daily has been used in clinical trials evaluating the protective effect on cancer biomarkers. 32 , 33 Preparation methods affect bioavailability of active chemical compounds and relevant endogenous enzymes. 7 , 8
Broccoli sprouts were given in dosages of up to 50 g/day (approximately glucosinolate 300 mcg) in 3 divided doses in a phase 1 clinical trial. 29 The most effective dosages for DIM in cancer treatment/prevention have yet to be determined. Some pharmacokinetic studies have been conducted in healthy adults, and DIM has been used in clinical studies in children. 37 , 39 In clinical trials, DIM has been used at doses of 2 to 5 mg/kg/day for short periods of time (up to 6 months). 17 , 41 DIM has been delivered via an aerosol in a study in lung cancer. 46
Information regarding safety and efficacy in pregnancy and lactation is lacking. Due to the potential effect on estrogen and androgen metabolism, as well as antiproliferative effects, DIM should not be taken during pregnancy. 16
Information on clinical interactions is lacking. Broccoli may antagonize the effect of warfarin; however, the effect of the vitamin K content in broccoli on INR fluctuations has been challenged because bioavailability is poor. 47
Sulforaphane is a potent phase 2 enzyme inducer, impacting the cytochrome P450 system, and has been observed to inhibit CYP3A4, an isozyme commonly involved in drug-drug interactions. 7 Sulforaphane restored chemosensitivity in doxorubicin-tolerant cell lines; therefore, an interaction with broccoli may present an advantage. 4
Theoretically, consumption of DIM as a supplement might interfere with oral contraception. 16
Clinical studies with I3C and DIM report mild GI adverse events and, rarely, rash and increases in liver enzymes. 14
The breakdown of certain glucosinolates has been demonstrated to have negative effects on the thyroid in animals, with goiters reported. 2 In a phase 1 safety trial, notable changes were observed for thyroid-stimulating hormone levels that exceeded upper limits of normal, but these did not reach statistical significance. 29 Changes in plasma ALT were also noted in placebo and active arms, but the effect was attributed to elevations usually observed by participants in such trials. 29
At 3 times the human therapeutic dose of DIM 2 mg/kg/day, no changes in serum chemistry or histology of the liver, kidney, and bone were found in immature rats 48 ; however, a study conducted in neonatal mice found toxic effects on the immune system, including the spleen. 28 Tumor-promoting effects of DIM have been shown in some animal models, especially at higher dosages. 15 , 49 Toxicity of DIM has been shown in dogs at 450 mg/kg/day. 17
Bibliography1. Brassica oleracea L. USDA, NRCS. 2012. The PLANTS Database ( http://plants.usda.gov , 8 March 2012). National Plant Data Team, Greensboro, NC 27401-4901 USA. Accessed March 8, 2012.
2. Moreno DA, Carvajal M, López-Berenguer C, García-Viguera C. Chemical and biological characterisation of nutraceutical compounds of broccoli. J Pharm Biomed Anal . 2006;41(5):1508-1522.
3. Finley JW. Reduction of cancer risk by consumption of selenium-enriched plants: enrichment of broccoli with selenium increases the anticarcinogenic properties of broccoli. J Med Food . 2003;6(1):19-26.
4. Fimognari C, Lenzi M, Hrelia P. Interaction of the isothiocyanate sulforaphane with drug disposition and metabolism: pharmacological and toxicological implications. Curr Drug Metab . 2008;9(7):668-678.
5. Safe S, Papineni S, Chintharlapalli S. Cancer chemotherapy with indole-3-carbinol, bis(3′-indolyl)methane and synthetic analogs. Cancer Lett . 2008;269(2):326-338.
6. Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle . 2005;4(9):1201-1215.
7. Jeffery EH, Keck AS. Translating knowledge generated by epidemiological and in vitro studies into dietary cancer prevention. Mol Nutr Food Res . 2008;52(suppl 1):S7-S17.
8. Rungapamestry V, Duncan AJ, Fuller Z, Ratcliffe B. Effect of meal composition and cooking duration on the fate of sulforaphane following consumption of broccoli by healthy human subjects. Br J Nutr . 2007;97(4):644-652.
9. Clarke JD, Dashwood RH, Ho E. Multi-targeted prevention of cancer by sulforaphane. Cancer Lett . 2008;269(2):291-304.
10. Juge N, Mithen RF, Traka M. Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cell Mol Life Sci . 2007;64(9):1105-1127.
11. Myzak MC, Dashwood RH. Chemoprotection by sulforaphane: keep one eye beyond Keap1. Cancer Lett . 2006;233(2):208-218.
12. Lampe JW, Peterson S. Brassica, biotransformation and cancer risk: genetic polymorphisms alter the preventive effects of cruciferous vegetables. J Nutr . 2002;132(10):2991-2994.
13. Beecher CW. Cancer preventive properties of varieties of Brassica oleracea : a review. Am J Clin Nutr . 1994;59(5)(suppl):1166S-1170S.
14. Minich DM, Bland JS. A review of the clinical efficacy and safety of cruciferous vegetable phytochemicals. Nutr Rev . 2007;65(6, pt 1):259-267.
15. Rogan EG. The natural chemopreventive compound indole-3-carbinol: State of the science. In Vivo . 2006;20(2):221-228.
16. By the way, doctor. A preventive doctor told me to take indolplex (bioavailable diindolylmethane or DIM) to aid estrogen metabolism. Is there any research available about this supplement? Harv Womens Health Watch . 2005;12(6):8.
17. Rajoria S, Suriano R, Parmar PS, et al. 3,3'-diindolylmethane modulates estrogen metabolism in patients with thyroid proliferative disease: A pilot study. Thyroid . 2011;21(3):299-304.
18. Ahmad A, Sakr WA, Rahman KM. Anticancer properties of indole compounds: Mechanism of apoptosis induction and role in chemotherapy. Curr Drug Targets . 2010;11(6):652-666.
19. Jin Y. 3,3'-diindolylmethane inhibits breast cancer cell growth via miR-21-mediated Cdc25A degradation. Mol Cell Biochem . 2011;358(1-2):345-354.
20. Le HT, Schaldach CM, Firestone GL, Bjeldanes LF. Plant-derived 3,3'-diindolylmethane is a strong androgen antagonist in human prostate cancer cells. J Biol Chem . 2003;278(23):21136-21145.
21. Kristal AR, Lampe JW. Brassica vegetables and prostate cancer risk: a review of the epidemiological evidence. Nutr Cancer . 2002;42(1):1-9.
22. Wang L, Lee IM, Zhang SM, Blumberg JB, Buring JE, Sesso HD. Dietary intake of selected flavonols, flavones, and flavonoid-rich foods and risk of cancer in middle-aged and older women. Am J Clin Nutr . 2009;89(3):905-912.
23. Gates MA, Tworoger SS, Hecht JL, DeVivo I, Rosner B, Hankinson SE. A prospective study of dietary flavonoid intake and incidence of epithelial ovarian cancer. Int J Cancer . 2007;121(10):2225-2232.
24. Kirsh VA, Peters U, Mayne ST, et al. Prospective study of fruit and vegetable intake and risk of prostate cancer. J Natl Cancer Inst . 2007;99(15):1200-1209.
25. Ambrosini GL, de Klerk NH, Fritschi L, Mackerras D, Musk B. Fruit, vegetable, vitamin A intakes, and prostate cancer risk. Prostate Cancer Prostatic Dis . 2008;11(1):61-66.
26. Firestone GL, Sundar SN. Minireview: Modulation of hormone receptor signaling by dietary anticancer indoles. Mol Endocrinol . 2009;23(12):1940-1947.
27. Shilling AD, Carlson DB, Katchamart S, Williams DE. 3,3'-diindolylmethane, a major condensation product of indole-3-carbinol, is a potent estrogen in the rainbow trout. Toxicol Appl Pharmacol . 2001;170(3):191-200.
28. Roh YS, Cho A, Islam MR, et al. 3,3'-diindolylmethane induces immunotoxicity via splenocyte apoptosis in neonatal mice. Toxicol Lett . 2011;206(2):218-228.
29. Shapiro TA, Fahey JW, Dinkova-Kostova AT, et al. Safety, tolerance, and metabolism of broccoli sprout glucosinolates and isothiocyanates: a clinical phase I study. Nutr Cancer . 2006;55(1):53-62.
30. Moore LE, Brennan P, Karami S, et al. Glutathione S-transferase polymorphisms, cruciferous vegetable intake and cancer risk in the Central and Eastern European Kidney Cancer Study. Carcinogenesis . 2007;28(9):1960-1964.
31. Gasper AV, Al-Janobi A, Smith JA, et al. Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli [published correction in Am J Clin Nutr . 2006;83(3):724]. Am J Clin Nutr . 2005;82(6):1283-1291.
32. Fowke JH, Longcope C, Hebert JR. Brassica vegetable consumption shifts estrogen metabolism in healthy postmenopausal women. Cancer Epidemiol Biomarkers Prev . 2000;9(8):773-779.
33. Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. Pilot study: effect of 3,3′-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer . 2004;50(2):161-167.
34. Thomson CA, Rock CL, Caan BJ, et al. Increase in cruciferous vegetable intake in women previously treated for breast cancer participating in a dietary intervention trial. Nutr Cancer . 2007;57(1):11-19.
35. Traka M, Gasper AV, Melchini A, et al. Broccoli consumption interacts with GSTM1 to perturb oncogenic signalling pathways in the prostate. PLoS One . 2008;3(7):e2568.
36. Bradlow HL, Zeligs MA. Diindolylmethane (DIM) spontaneously forms from indole-3-carbinol (I3C) during cell culture experiments. In Vivo . 2010;24(4):387-391.
37. Banerjee S, Kong D, Wang Z, Bao B, Hillman GG, Sarkar FH. Attenuation of multi-targeted proliferation-linked signaling by 3,3'-diindolylmethane (DIM): From bench to clinic. Mutat Res . 2011;728(1-2):47-66.
38. Del Priore G, Gudipudi DK, Montemarano N, Restivo AM, Malanowska-Stega J, Arslan AA. Oral diindolylmethane (DIM): Pilot evaluation of a nonsurgical treatment for cervical dysplasia. Gynecol Oncol . 2010;116(3):464-467.
39. Heath EI, Heilbrun LK, Li J, et al. A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3'- diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. Am J Transl Res . 2010;2(4):402-411.
40. Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. Pilot study: Effect of 3,3'-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer . 2004;50(2):161-167.
41. Castanon A, Tristram A, Mesher D, et al. Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: Double-blind, randomised, controlled trial. Br J Cancer . 2012;106(1):45-52.
42. Galan MV, Kishan AA, Silverman AL. Oral broccoli sprouts for the treatment of Helicobacter pylori infection: a preliminary report. Dig Dis Sci . 2004;49(7-8):1088-1090.
43. Opekun AR, Yeh CW, Opekun JL, Graham DY. In vivo tests of natural therapy, Tibetan yogurt or fresh broccoli, for Helicobacter pylori infection. Methods Find Exp Clin Pharmacol . 2005;27(5):327-329.
44. Murashima M, Watanabe S, Zhuo XG, Uehara M, Kurashige A. Phase 1 study of multiple biomarkers for metabolism and oxidative stress after one-week intake of broccoli sprouts. Biofactors . 2004;22(1-4):271-275.
45. Riedl MA, Saxon A, Diaz-Sanchez D. Oral sulforaphane increases Phase II antioxidant enzymes in the human upper airway. Clin Immunol . 2009;130(3):244-251.
46. Ichite N, Chougule M, Patel AR, Jackson T, Safe S, Singh M. Inhalation delivery of a novel diindolylmethane derivative for the treatment of lung cancer. Mol Cancer Ther . 2010;9(11):3003-3014.
47. Schurgers LJ, Shearer MJ, Hamulyák K, Stöcklin E, Vermeer C. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects. Blood . 2004;104(9):2682-2689.
48. Elackattu AP, Feng L, Wang Z. A controlled safety study of diindolylmethane in the immature rat model. Laryngoscope . 2009;119(9):1803-1808.
49. Reed GA, Sunega JM, Sullivan DK, et al. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3'-diindolylmethane in healthy subjects. Cancer Epidemiol Biomarkers Prev . 2008;17(10):2619-2624.
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