Scientific Name(s): Brassica oleracea L. var. botrytis L.
Common Name(s): BioResponse, Broccoli, Calabrese, Chou broccoli, Common broccoli, Cruciferous vegetable, Di-indolylmethane (DIM), Indole-3-carbinol (I3C), Indolplex, Sprouting broccoli
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 Pharmacology
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.21
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, 28
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, 41
A randomized, double-blind, placebo-controlled trial evaluated the effects of broccoli sprout-derived sulforaphane on behavior in 40 young men (age, 13 to 27 years) with moderate to severe autism spectrum disorder (ASD). Sulforaphane (50 to 150 mcmol daily for 18 weeks) was found to safely and effectively improve core aberrant behaviors of ASD at 4-, 10- and 18-week follow ups, which tended to revert to baseline after cessation of therapy. Two patients on sulforaphane experienced a single episode of unprovoked seizure.50
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
Pregnancy / Lactation
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 rats48; 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
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