Summary

Introduction

Cruciferous or Brassica vegetables are so named because they come from plants in the family known to botanists and biologists as Cruciferae or alternately, Brassicaceae. The Brassicaceae family, which includes the model plant Arabidopsis thaliana, comprises approximately 375 genera and over 3,000 species (1). Many commonly consumed cruciferous vegetables come from the Brassica genus, including broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, kale, kohlrabi, mustard, rutabaga, turnips, bok choy, and Chinese cabbage (2). Examples of edible crucifers from other genera within the Brassicaceae family include radish (Raphanus sativus), horseradish (Armoracia rusticana), watercress (Nasturtium officinale), wasabi (Wasabia japonica), and Swiss chard (Beta vulgaris flavescens) (2).

 

Cruciferous vegetables are unique in that they are a rich source of sulfur-containing compounds called glucosinolates (β-thioglucoside N-hydroxysulfates) that impart a pungent aroma and spicy (some say bitter) taste (Figure 1). Glucosinolates can be classified into three categories based on the chemical structure of their amino acid precursors: aliphatic glucosinolates (e.g., glucoraphanin), indole glucosinolates (e.g., glucobrassicin), and aromatic glucosinolates (e.g., gluconasturtiin) (Figure 1) (1). Around 130 glucosinolate structures have been described to date (3), but only a subset can be found in the human diet. In a cohort of 2,121 German participants in the European Prospective Investigation into Cancer and Nutrition (EPIC study), glucobrassicin, sinigrin, glucoraphasatin (dehydroerucin), glucoraphanin, and glucoiberin were found to contribute most to total glucosinolate intake (4).

Glucosinolates and their breakdown derivatives (metabolites), especially isothiocyanates and indole-3-carbinol, exert a variety of biological activities that may be relevant to health promotion and disease prevention in humans (see the MIC articles on Indole-3-Carbinol and Isothiocyanates).

Figure 1. Chemical Structures of Some Glucosinolates. Chemical structures of aliphatic glucosinolates, including sinigrin, glucoiberin, glucoraphasatin, glucoraphanin, and progoitrin. Chemical structures of two aromatic glucosinolates, glucotropaeolin and gluconasturtiin. Chemical structure of the indole glucosinolate, glucobrassicin. Plants synthesize glucosinolates from amino acids. Glucosinolates can be classified based on their amino acid precursors. Aliphatic glucosinolates are derived from alanine, leucine, isoleucine, valine, and methione. Aromatic glucosinolates are derived from phenylalanine or tyrosine, and tryptophan is the precursor of indole glucosinolates (ishida, 2014).

[Figure 1 - Click to Enlarge]

Metabolism and Bioavailability of Glucosinolates

Metabolism

The hydrolysis of glucosinolates, which is catalyzed by a class of enzymes called myrosinases (β-thioglucosidases), leads to the formation of breakdown compounds, such as thiocyanates, isothiocyanates, indoles, oxazolidine-2-thiones (e.g., goitrin), epithionitrile, and nitrile (Figure 2). In intact plant cells, myrosinase is physically separated from glucosinolates. Yet, when plant cells are damaged, myrosinase is released and comes in contact with glucosinolates, catalyzing their conversion into highly reactive metabolites. In plants, thiocyanates, isothiocyanates, epithionitrile, and nitrile are defensive compounds against pathogens, insects, and herbivores (1). When raw cruciferous vegetables are chopped during the cooking process, glucosinolates are rapidly hydrolyzed by myrosinase, generating metabolites that are then absorbed in the proximal intestine. In contrast, boiling cruciferous vegetables before consumption inactivates myrosinase, thus preventing the breakdown of glucosinolates. A small fraction of intact glucosinolates may be absorbed in the small intestine, but a large proportion reaches the colon (5). Of note, boiling cruciferous vegetables has also been found to reduce their glucosinolate content to a much greater extent than steam cooking, microwaving, and stir-frying do (5). Nonetheless, when cruciferous vegetables are cooked, bacterial myrosinase-like activity in the colon is mainly responsible for glucosinolate degradation, generating a wide range of metabolites (5, 6).

A neutral pH may favor the formation of isothiocyanates from glucosinolates (Figure 2). Once absorbed, isothiocyanates, such as glucoraphanin-derived sulforaphane, are conjugated to glutathione in the liver, and then sequentially metabolized in the mercapturic acid pathway (Figure 3). Sulforaphane metabolites — sulforaphane-glutathione, sulforaphane-cysteine-glycine, sulforaphane-cysteine, and sulforaphane N-acetylcysteine (Figure 3) — collectively known as dithiocarbamates, are ultimately excreted in the urine (5).

Bioavailability

The composition and content of glucosinolates in cruciferous vegetables are relatively stable, yet depend on the genus and species and can vary with plant growing and post-harvest storage conditions and culinary processing (7, 8). Since most cruciferous vegetables are cooked prior to eating, bacterial myrosinase-like activity in the gut rather than plant myrosinase is responsible for the initial step in glucosinolate degradation (Figure 2). In a feeding study involving 45 healthy subjects, the mean conversion rate of glucosinolates (of which 85% was glucoraphanin) to dithiocarbamates over a 24-hour period was estimated to be around 12% with wide variations among participants (range, 1.1 to 40.7%) (7). In contrast, 70%-75% of ingested isothiocyanates were found to be metabolized to dithiocarbamates. Therefore, following the ingestion of cooked cruciferous vegetables, the conversion of glucosinolates into isothiocyanates by gut bacteria appears to be a limiting step in the generation of dithiocarbamates (7). However, differences in individuals’ capacity to metabolize glucosinolates have not been linked to differences in gut microbiota composition (9).

Figure 2. Breakdown of Glucosinolates. Glucosinolate is metabolized to glucosinolatethiohydroximate-O-sulfonate via myrosinase. In neutral pH, isothiocyanate can be formed, or oxazolidine-2-thione (via the unstable intermediate beta-OH-isothiocyanate), or indole-3-carbinol (via the unstable intermediate, indol-3-ylmethyl-isothiocyanate). In acidic pH, the compounds epithionitrile or nitrile can be formed. Figure adapted from Holst et al. (2004).

[Figure 2 - Click to Enlarge]

Figure 3. Metabolism of Glucoraphanin via the Mercapturic Acid Pathway. Glucoraphanin is metabolized by myrosinase to sulforaphane; sulforaphane is converted to sulforaphane-gluathione conjugate, then to sulforaphane-cysteine-glcine, then to sulforaphane-cysteine, then to sulforaphane N-acetylcysteine

[Figure 3 - Click to Enlarge]

Disease Prevention

Like most other vegetables, cruciferous vegetables are good sources of a variety of nutrients and phytochemicals that synergistically contribute to health promotion (see Bioactive compounds in cruciferous vegetables) (10). One challenge in studying the relationships between cruciferous vegetable intake and disease risk in humans is dissociating the benefits of whole diets that are generally rich in vegetables from those that are specifically rich in cruciferous vegetables (11). One characteristic that sets cruciferous vegetables apart from other vegetables is their high glucosinolate content (see Introduction). Glucosinolate hydrolysis products may play important roles in disease prevention by triggering antioxidant and anti-inflammatory response and contributing to the maintenance of cell homeostasis (see the MIC articles on Isothiocyanates and Indole-3-Carbinol).

Genetic influences

Once absorbed, glucosinolate-derived isothiocyanates (like sulforaphane) are promptly conjugated to glutathione by a class of phase II detoxification enzymes known as glutathione S-transferases (GSTs) (Figure 3). This mechanism is meant to increase the solubility of isothiocyanates, thereby promoting a rapid excretion in the urine. Isothiocyanates are thought to play a prominent role in the potential anticancer and cardiovascular benefits associated with cruciferous vegetable consumption (12, 13). Genetic variations in the sequence of genes coding for GSTs may affect the activity of these enzymes. Such variations have been identified in humans. Specifically, null variants of the GSTM1 and GSTT1 alleles contain large deletions, and individuals who inherit two copies of the GSTM1-null or GSTT1-null alleles cannot produce the corresponding GST enzymes (14). It has been proposed that a reduced GST activity in these individuals would slow the rate of excretion of isothiocyanates, thereby increasing tissue exposure to isothiocyanates after cruciferous vegetable consumption (15). However, human interventional studies with watercress report there is no difference in the isothiocyanate excretion rate between positive (+/+) and null (-/-) genotypes (16). Similar studies with broccoli have shown that GSTM1-/- individuals excreted a greater proportion of ingested sulforaphane via mercapturic acid metabolism than GSTM1+/+ individuals (17, 18). In addition, GSTs are involved in "detoxifying" potentially harmful substances like carcinogens, suggesting that individuals with reduced GST activity might also be more susceptible to cancer (19-21). Finally, induction of the expression and activity of GSTs and other phase II detoxification/antioxidant enzymes by isothiocyanates is an important defense mechanism against oxidative stress and damage associated with the development of diseases like cancer and cardiovascular disease (22). The ability of sulforaphane (glucoraphanin-derived isothiocyanate) to reduce oxidative stress in different settings is linked to activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway. Yet, whether potential protection conferred by isothiocyanates via the Nrf2-dependent pathway is diminished in individuals carrying GST-/- variants is currently unknown.

Some, but not all, observational studies have found that GST genotypes could influence the associations between isothiocyanate intake from cruciferous vegetables and risk of disease (23).

Cardiovascular disease

High intakes of fruit and vegetables have been consistently associated with a reduced risk of cardiovascular disease (CVD) (24, 25). Yet, few observational studies have specifically examined the potential benefits of cruciferous vegetable consumption. In the Shanghai Women’s Health Study (mean follow-up, 10.2 years) and the Shanghai Men’s Health Study (mean follow-up, 4.6 years), which included a total of 134,796 Chinese adults, participants in the highest versus lowest quintile of cruciferous vegetable intakes had a 22% reduced risk of all cause-mortality and a 31% reduced risk of CVD-related mortality (26). In contrast, a pooled analysis of two large US prospective cohort studies, the Nurses’ Health Study (70,870 women) and the Health Professionals’ Follow-Up Study (38,918 men), found no significant association between cruciferous vegetable intake and combined risk of myocardial infarction (MI) and ischemic stroke (27). A case-control study conducted in 2,042 subjects (ages, <75 years) who survived a first acute myocardial infarction (MI), and matched healthy controls with no CVD history found that the individuals in the highest versus lowest tertile of cruciferous vegetable intakes (6 times/week versus <1 time/week) had 27% lower odds of MI (28). However, further analyses showed that the association between cruciferous vegetable intake and MI events was significant in individuals with two functional GSTT1 alleles but not in carriers of two alleles of the GSTT1 null variant (-/-) (28).

Analysis of data from two 12-week randomized controlled trials in 130 participants with mild or moderate CVD risk found that the consumption of 400 g/week of high-glucosinolate broccoli (containing 3 to 6 times more glucoraphanin and glucoiberin than standard broccoli) resulted in a significant reduction in low-density lipoprotein (LDL)-cholesterol concentration in plasma compared with standard broccoli (29). Whether the effect of glucosinolates on cholesterol metabolism might be beneficial in the prevention of CVD needs further investigation.

Cancer

A recent intervention study demonstrated that cruciferous vegetables could increase the detoxification of carcinogens and other xenobiotics in humans. In this 12-week randomized controlled trial in 391 healthy Chinese adults exposed to high levels of air pollution, daily consumption of a broccoli sprout-rich beverage (providing 600 µmol/day of glucoraphanin and 40 µmol/day of sulforaphane) significantly increased the urinary excretion of a known carcinogen, benzene, and a toxicant, acrolein, compared to placebo (20). The biological activities of glucosinolate derivatives, isothiocyanates and indole-3-carbinol, which include modulation of xenobiotic metabolism, but also antioxidant and anti-inflammatory properties, induction of cell cycle arrest and apoptosis, and inhibition of angiogenesis, likely contribute to the potential benefits of cruciferous vegetables in the prevention of cancer (see the MIC articles on Isothiocyanates and Indole-3-Carbinol) (23).

Evidence from observational studies

Numerous observational studies have examined the relationship between cruciferous vegetable intake and cancer risk. Results from recent published meta-analyses of observational studies are reported in Table 1 (adapted from 23). 

Table 1. Cruciferous Vegetables and Cancer Risk: Meta-analyses of Observational Studies
Type of Cancer Type of Observational Studies Relative Risk [RR] or Odds Ratio [OR] (95% Confidence Interval) Relative Risk [RR] in Subgroup Analyses (e.g., by food group or study type) References
Bladder cancer 5 prospective cohort and 5 case-control studies  RR: 0.80 (0.69-0.92) RR: 0.78 (0.67-0.89) with case-control studies only
RR: 0.86 (0.61-1.11) with cohort studies only 
Liu et al. (2013) (30)
12 prospective cohort and case-control studies RR: 0.84 (0.77-0.91)   Yao et al. (2014) (31)
7 prospective cohort and case-control studies RR: 0.85 (0.69-1.06)   Vieira et al. (2015) (32) 
8 prospective cohort studies RR: 0.97 (0.93-1.01)   Xu et al. (2015) (33)
Breast cancer 11 case-control studies RR: 0.85 (0.77-0.94)   Liu et al. (2013) (34)
Colorectal cancer 24 case-control and 11 prospective cohort studies RR: 0.82 (0.75-0.90) RR: 0.76 (0.60-0.97) for studies reporting on cabbage intake
RR: 0.82 (0.65-1.02) for studies reporting on broccoli intake
Wu et al. (2013) (35)
11 prospective cohort and 18 case-control studies OR: 0.92 (0.83-1.01) OR: 0.84 (0.72-0.98) for colon cancer
OR: 0.99 (0.67-1.46) for rectal cancer
OR: 1.09 (0.90-1.33) for colonic adenoma
OR: 0.80 (0.65-0.99) for studies reporting on broccoli intake
OR: 0.95 (0.80-1.14) for studies reporting on cabbage intake
OR: 1.0 (0.75-1.34) for studies reporting on Brussels sprouts
Tse et al. (2014) (36)
Endometrial cancer 1 prospective cohort study and 16 case-control studies OR: 0.79 (0.69-0.90) per 100 g/day   Bandera et al. (2007) (37)
Gastric cancer 6 prospective cohort and 16 case-control studies RR: 0.81 (0.75-0.88) RR: 0.78 (0.71-0.86) for case-control studies
RR: 0.89 (0.77-1.02) for cohort studies
RR: 0.68 (0.58-0.80) for studies reporting on cabbage intake
Wu et al. (2013) (38)
Lung cancer 6 prospective cohort and 13 case-control studies   RR: 0.77 (0.68-0.88) for case-control studies
RR: 0.83 (0.62-1.08) for cohort studies
Lam et al. (2009) (39)
5 prospective cohort and 6 case-control studies RR: 0.75 (0.63-0.89)   Wu et al. (2013) (40)
Ovarian cancer 5 prospective cohort and 6 case-control studies RR: 0.90 (0.82-0.98) RR: 0.84 (0.75-0.94) for case-control studies
RR: 1.0 (0.85-1.11) for cohort studies
Han et al. (2014) (41)
4 prospective cohort and 4 case-control studies RR: 0.89 (0.81-0.99)   Hu et al. (2015) (42)
Pancreatic cancer 4 prospective cohort and 5 case-control studies  OR: 0.79 (0.64-0.91)  OR: 0.72 (0.55-0.89) for case-control studies
OR: 0.87 (0.67-1.06) for cohort studies
OR: 0.78 (0.55-1.01) for high-quality studies
OR: 0.80 (0.66-0.94) for low-quality studies 
Li et al. (2015) (43)
Prostate cancer 7 prospective cohort and 6 case-control studies  RR: 0.90 (0.85-0.96) RR: 0.79 (0.69-0.89) for case-control studies
RR: 0.95 (0.89-1.02) for cohort studies 
Liu et al. (2012) (44)
Renal cell carcinoma 6 prospective cohort and 6 case-control studies  RR: 0.81 (0.72-0.91)  RR: 0.89 (0.82-0.98) for high-quality studies
RR: 0.72 (0.64-0.81) for case-control studies
RR: 0.92 (0.84-1.00) for cohort studies 
Zhao et al. (2013) (45)
3 prospective cohort and 7 case-control studies  RR: 0.73 (0.63-0.83) RR: 0.69 (0.60-0.78) for case-control studies
RR: 0.96 (0.71-1.21) for cohort studies 
Liu et al. (2013) (46)

Most meta-analyses found inverse associations between cruciferous vegetable intake and risk of bladder, breast, colorectal, endometrial, gastric, lung, ovarian, pancreatic, prostate, and renal cancer. Subgroup analyses showed that inverse associations remained significant in pooled analyses of case-control studies but not in pooled analyses of prospective cohort studies (see Table 1). Retrospective case-control studies are susceptible to bias in the selection of participants (cases and controls) and prone to dietary recall bias compared to prospective cohort studies, which collect dietary information from participants before they are diagnosed with cancer (47). The method of cooking cruciferous vegetables, which strongly affects the bioavailability and potential anticancer benefits of isothiocyanates (see Metabolism and Bioavailability of Glucosinolates) may be a source of bias and explain variation in the results of the studies (heterogeneity among studies). The lack of information regarding cooking methods prevented data adjustment to reduce bias.

In the past decades, some observational studies have examined the effect of individuals’ genetic variations on the relationship between cruciferous vegetable intake and the risk of different cancer types. For example, a pooled analysis of two prospective cohort studies and six case-control studies found an inverse association between cruciferous vegetable consumption and risk of colorectal neoplasm in carriers of the GSTT1 null variant but not in individuals with the GSTM1 null variant or those with both the GSTT1and GSTM1 null variants (-/-) (36). The results of a pooled analysis of five case-control studies also suggested a stronger association between cruciferous vegetable intake and lung cancer in carriers of both the GSTT1-/- and GSTM1-/- variants compared to carriers of wild-type alleles (+/+); however, it was not reported whether results from these two groups of individuals were significantly different (39). There is also a significant body of evidence suggesting that GSTM1+/+ individuals gain greater cancer protection from consumption total cruciferous vegetables or broccoli compared to GSTM1-/- variant carriers (25, 48, 49). Current evidence is scarce, and adequately powered, well-designed studies are required to assess and explain potential interactions between cruciferous vegetable intake and GST genotypes.

A few observational studies have looked at whether cruciferous vegetable intake could be associated with reduced risks of disease progression and mortality. The highest versus lowest intake of cruciferous vegetables (assessed before diagnosis) was associated with a better survival rate over 72 months after diagnosis in 547 women with lung cancer (50). A prospective study in 29,361 men who underwent a prostate-specific antigen (PSA) test found that intake of cruciferous vegetables was inversely associated with risk of metastatic prostate cancer — cancer that has spread beyond the prostate (i.e., late-stage prostate cancer) — during a mean follow-up of 4.2 years (51). Another prospective study in 1,560 men diagnosed with non-metastatic prostate cancer reported that higher post-diagnosis intake of cruciferous vegetables was associated with a 59% lower risk of prostate cancer progression during a two-year period after completion of the dietary assessment (52). In contrast, cruciferous vegetable consumption in a cohort of 11,390 women with stage I-III invasive breast cancer (from four US and Chinese prospective studies), assessed about two years after diagnosis, was not found to be associated with risk of cancer recurrence or total mortality (53)

Nutrient Interactions

Iodine and thyroid function

Very high intakes of cruciferous vegetables, such as cabbage and turnips, have been found to cause hypothyroidism (insufficient production of thyroid hormones) in animals (54). Two mechanisms can potentially explain this effect. The hydrolysis of progoitrin, found in cruciferous vegetables (see Figure 1), may yield a compound known as goitrin, which may interfere with thyroid hormone synthesis. The hydrolysis of another class of glucosinolates, known as indole glucosinolates, results in the release of thiocyanate ions (see Figure 2) that can compete with iodine for uptake by the thyroid gland (55). However, increased exposure to thiocyanate ions from cruciferous vegetable consumption or, more commonly, from cigarette smoking, does not appear to increase the risk of hypothyroidism unless accompanied by iodine deficiency. One study in humans found that the consumption of 150 g/day (5 oz/day) of cooked Brussels sprouts for four weeks had no adverse effects on thyroid function (56). Similarly, consumption of high amounts of cruciferous vegetables has been associated with increased thyroid cancer risk only in iodine-deficient areas (57).

Intake Recommendations

The 2015-2020 Dietary Guidelines for Americans recommend eating a variety of vegetables daily (2½ cup-equivalents/day for a 2,000 calorie diet) from all of the five vegetable subgroups (dark green, red and orange, legumes, starchy, and other; see 58). No separate recommendations have been established for cruciferous vegetables, yet the 2015-2020 Dietary Guidelines for Americans recommend that adults consume 1½-2½ cup-equivalents of dark-green vegetables (which include cruciferous vegetables) per week (58).

Bioactive compounds in cruciferous vegetables

Cruciferous vegetables are important sources of some vitamins and minerals, fiber, and various phytochemicals other than glucosinolates (Table 2). Many of these compounds likely contribute to the potential health-promoting benefits of cruciferous vegetables.

Table 2. Some Potentially Beneficial Compounds in Cruciferous (Brassica) Vegetables
Vitamins Minerals Phytochemicals
Folate Potassium Carotenoids
Vitamin C Selenium Chlorophyll
Vitamin K Calcium Fiber
    Flavonoids
    Indole-3-Carbinol
    Isothiocyanates
    Lignans
    Phytosterols
    Sulfur bioactives (other than glucosinolates) (59)

Authors and Reviewers

Originally written in 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2016 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in April 2017 by:
Maria Traka, Ph.D.
Senior Research Scientist
Chair of the Athena SWAN SAT
Food and Health Programme
Institute of Food Research
Norwich, United Kingdom

Copyright 2005-2017  Linus Pauling Institute


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