"Functional foods," "nutraceuticals," "designer foods" and "medicinal foods" are terms that describe foods, and key ingredients isolated from foods, that have non-nutritive or tertiary functional properties. Researchers, healthcare practitioners, laypersons, and the popular media use these words interchangeably. The purpose of this article is to review the medicinal properties inherent in food sources of folate, a known anticolon cancer nutrient, and to discover other nutritive factors (such as glutamine, glucosinolates, and fiber) within those same foods that support colon health and maintain intestinal integrity.
There is substantial evidence to indicate that sufficient levels of folate in the daily diet can prevent or at least reduce the incidence and onset of colorectal cancer. Afolate deficiency can cause and promote DNA mutations by increasing DNA's susceptibility to damage by carcinogenic compounds, while sufficient levels of folate in the body can reduce the risk of clinically evident colon cancer. (2) In 1998, a follow up of the famous Nurses' Health Study completed on 88,756 female nurses found that 15 years of high folate intake (> 400 mcg/day) was associated with a 75% reduction in risk for colon cancer.(3) This was a prospective cohort study with a very large sample size, and the resultant data was adjusted for alcohol intake, age, physical activity, red meat consumption, fiber intake, smoking history, family history and even aspirin use.
Another cohort study investigated the relative risk for colon cancer in men, based on folate intake. The National Health and Nutrition Examination Survey (NHANES) Follow-up Study (NHEFS)(4) found that the relative risk of colon cancer for participants in the study was 60% less in those men that ingested over 239 meg of folate in their diet per day as compared to those men that took in less than 103.3 mcg of folate per day.
Whole food sources of folate range from chicken liver (770 mcg per 3.5 oz) to cooked lentils (180 mcg per 1/2 cup), Brussels sprouts (47 mcg per 1/2 cup) and broccoli (39 mcg per 1/2 cup). Interestingly,' key vegetable sources of folate, such as cruciferous vegetables and beets, contain additional compounds specific for reducing colon cancer risk and supporting intestinal health, such as glutamine, glucosinolates, and fiber.
Cruciferous Vegetables and Colon Cancer
In addition to the folate-related actions that cruciferous vegetables (e.g., kale, Brussels sprouts, cabbage and broccoli) have on preventing or reducing the risk of colorectal cancer, these vegetables also contain glucosinolate compounds that cause a coordinated metabolic induction of many of the Phase II liver detoxification enzymes. These enzymes detoxify carcinogenic compounds from the body, thus reducing the susceptibility of colon cells to DNA damage. Glutathione transferases, NAD(P)H, quinone oxidoreductase, glucuronosyltransferase, and epoxide hydrolase are all Phase II enzymes that inactivate environmental carcinogens known to increase one's risk of developing colon cancer.
Phase II Detoxification Enzyme inducers that Reduce the Risk of Developing Colon Cancer
Phase II enzymes inactivate carcinogens in one of two ways: either through the destruction of the reactive centers of the compounds, or, more often, by conjugation with endogenous ligands, thereby counteracting the toxic properties associated with the carcinogen, and quickening their elimination from the body. Cruciferous vegetables contain water-soluble secondary metabolites referred to as glucosinolate compounds.
Glucosinolates found in cruciferous vegetables are converted by endogenous enzymes into isothiocyanates when they are chewed, crushed in the presence of water, or otherwise injured. This conversion is a natural defense response to predatory and other destructive influences. The tissue damage more specifically results in the release of the endogenous enzyme myrosinase, or thioglucosidase, which cleaves the glucoside bond. This results in an unstable intermediate which rearranges to release sulfate, isothiocyanates and other products.
The isothiocyanates are the principal inducers of Phase II liver detoxification enzymes. Sulforaphane and sinigrin are two isothiocyanates that protect against, and oftentimes reduce, the severity of colon cancer.(5) Sulforaphane supports the enzymatic activity that takes place in Phase I liver detoxification and assists the liver in carrying out the Phase II conjugation pathways. Sinigrin complements the activity of sulforaphane by also stimulating the Phase II detoxification system. In addition to supporting the liver detoxification system, sinigrin stimulates apoptosis, a process that naturally causes a damaged cell to fragment into membrane-bound particles that are then eliminated by phagocytosis.(6) Organosulfur compounds such as dithiolethiones that are found in cruciferous vegetables are also considered putative detoxifying agents via their effect on Phase II enzymes.(7, 8)
Inducing Detoxification of Environmental Mutagens that Lead to Colon Cancer
Isothiocyanates have specifically been shown to induce the detoxification of environmental mutagens that can lead to colon cancer.(9)
Interestingly, 50% of people completely lack the glutathione-S-transferase M1 (GSTM1) enzyme due to a homozygous gene deletion. This enzyme is responsible for the rapid conjugation of isothiocyanates to glutathione for excretion (Phase II). Lin et al.(10) hypothesized that people with this mutation would maintain higher levels of isothiocyanates in the body due to decreased excretion and should show a lower incidence of colorectal adenomas, the precursors of colorectal cancer, if isothiocyanates are indeed anticarcinogenic. The researchers found that broccoli (39 mcg of folate per 1/2 cup) and kale were significantly associated with a lower prevalence of colorectal carcinomas in a sample of nearly a thousand people (459 adenoma cases and 507 controls sampled from patients undergoing cancer sigmoidoscopy screening in southern California). The presence of the GSTM1 null genotype alone did not significantly correlate with the occurrence of colorectal carcinoma. However, the GSTM1 null genotype did correlate wit h a significant reduction of incidence of colorectal carcinoma when it was covaried with broccoli and total cruciferous vegetable consumption (p=0.001 and p=0.02, respectively). The lowest incidence of colorectal carcinoma occurred in GSTM1 null individuals in the highest quartile of broccoli consumption, supporting the hypothesis that isothiocyanates in crucifers may be excreted more slowly in urine in GSTM1 individuals.
In addition to glucosinolate compounds, some crucifers contain significant levels of the amino acid glutamine, also important in supporting the detoxification system and maintaining optimal intestinal health.
Glutamine and Intestinal Health
Glutamine: Another Compound Found in Vegetable Sources of Folate (Cabbage and Beets) that Supports Intestinal Health
Glutamine is the most abundant amino acid in the blood stream (30-35% of amino acid nitrogen in plasma) and fills a number of detoxification-associated biochemical needs in the body.(11) It is a conditionally-essential amino acid, in that the human body produces it endogenously. Deficiencies are prevalent however, primarily because of impaired detoxification mechanisms, cancer, burns, trauma, chronic protein catabolism and excessive exercise.(12,13)
This amino acid is the main metabolic fuel for enterocytes of the small intestine, lymphocytes, macrophages, and fibroblasts and plays a major role in the first line of immune defense in the intestine as well as in the body as a whole. Interestingly, this supportive nutrient is found in particularly high concentrations in two vegetable sources recognized for their detoxifying properties and folate content: cabbage and beets.(14-18)
Research suggests that glutamine is essential to the health and maintenance of the intestinal tract, a vital organ of detoxification.(19,20) In fact, the intestine is the greatest user of glutamine in the body. The intestinal enterocytes absorb glutamine from the lumen of the gut and the bloodstream. The intestinal cell mitochondria then convert glutamine to glutamate, and then to alpha-ketoglutarate, which is used in the Krebs cycle for ATP production.
Studies have shown that the level of stored glutamine drops significantly in humans following surgery, trauma, or burns, as well as during sepsis.(21-23) It is well recognized that such conditions cause a state of imbalance of beneficial organisms in the intestinal tract.
Its deficiency has been implicated in immune dysfunction, a condition also associated with impaired detoxification mechanisms, because it serves as a main precursor of nucleotide synthesis and also as an energy source for rapidly dividing cells, such as immune cells following an immune threat.(24-26)
Prevention of Microbial Translocation
Glutamine's positive effect on the GI tract appears to be due to its use as a food source by both intestinal immune cells (lymphocyte-rich Peyer's patches) and mucosal cells. Intestinal epithelial cells contain very low levels of glutamine synthetase and hence are largely dependent on pre-formed glutamine, either from the diet or from the blood. If glutamine is lacking in the diet, or if a person is being fed parenterally due to illness, intestinal cells will take glutamine from the blood stream at the expense of muscle tissue, thus depleting the body's stores.(27) When levels of glutamine drop, intestinal epithelial cells and lymphocytes begin to lose function, compromising the integrity of the epithelium and leaving the intestine vulnerable to microbial translocation (passage of bacteria or toxins into the bloodstream via the intestinal wall) Several factors can disrupt intestinal permeability leading to increased microbial translocation, including:
- Impaired Detoxification Pathways
- Trauma
- Infection
- Starvation, and
- Chemotherapy
Bacteria, fungi, and other toxins can translocate across the weakened mucosal barrier into the bloodstream, where they react with the reticuloendothelial system, stimulating production of cytokines via the hypothalamic-pituitary-adrenal axis.(34) Cortisol is subsequently released from the adrenals, which increases glutaminase activity in intestinal enterocytes, thereby increasing breakdown of glutamine in the small intestine. This results in a progressive depletion of glutamine and glutathione (which contains glutamine) from skeletal muscle, leading to oxidative muscle tissue damage.
Additionally, glutamine increases intestinal glutathione synthetase activity,(25) improving the antioxidant capacity of the gut and increasing the mitogenic response to immune threats.(26) Gut-associated lymphoid tissue (GALT) requires glutamine for optimal function. GALT comprises the Peyer's patches and lymphoid follicles scattered throughout the intestinal mucosa. It is in this tissue that B and T immune cells are primed against intestinal antigens, thus forming a "frontline" defense of memory cells that can be seeded in distant mucosal effector sites. Maintenance of immune function and a healthy intestinal tract is vital to supporting one's ability to eliminate environmental toxins from the body.
Mechanisms of Action of Cabbage: A Food Source of Glutamine with Known Chemopreventive and Immunoprotective Properties
In addition to its glutamine (and folate and glucosinolate) content, other factors within cabbage contribute to its inherent immunoprotective and chemopreventive properties. Cabbage stimulates the production of tumor necrosis factor [alpha] (TNF) and interleukin-1 (IL-1), important players in antitumorial, antiviral, immunoregulatory, and inflammatory responses.(37) Further, cabbage contains glucosinolates and their breakdown products that alter the induction of glutathione S-transferase (GST), NADPH, and Quinone oxidoreductase (NQO),(38) thereby supporting detoxification of colon cancer-causing agents in the body.
The GST family of detoxification enzymes are responsible for conjugating electrophilic compounds with glutathione, creating a more water-soluble, and usually non-cytotoxic compound to be excreted. The flavoprotein NQO functions as a catalyst for the reduction of a wide range of quinones, quinone imines, and azo dyes via a two-electron transfer. Researchers speculate that the protective action of NQO is a result of its successful competition with single-electron reduction reactions and the inhibition of oxidative metabolic intermediates.(39) This augmentation in free radical production reduces the total burden placed on the immune system.(40)
Some of the known medicinal constituents in cabbage include 4-Me-glucobrassicin, progoitrin, 4-OH-glucobrassicin, R-goitrin, sinigrin, flavonoids, glucoiberin, gluconapin, thiocyanates, glutamine, isothiocyanates, phenolic compounds, and indole-3-carbinol.(41-43)
Maintenance of intestinal integrity and immune function
Komatsu et al.(44) administered cabbage juice to normal and hepatome-bearing rats. In this study, cabbage juice stimulated tumor necrosis factor [alpha] (TNF[alpha]) and interleukin-1 (IL-1) in the normal rats but failed to do so in the hepatome-bearing rats, whose levels of these enzymes were already elevated. The cabbage demonstrated immune stimulatory properties which the authors speculate was due to some "unknown" effective component that can be absorbed from the GI tract to stimulate production of TNF[alpha] and IL-1. This component may be glutamine, although other functional constituents within cabbage cannot be ruled out. TNF[alpha] and IL-1 are the primary cytokines produced by activated macrophages. Additionally TNF[alpha] plays an important role in antitumor, antiviral, immunoregulatory, and inflammatory responses.
Administering vegetables that contain glutamine, in addition to other known tertiary compounds (such as folate and glucosinolates), would likely offer a greater clinical effect on colon/intestinal health than the sum of the components in isolate form.(45) further example of a glutamine-rich food that contains complementary compounds such as folate and fiber that support colon health is beta vulgaris, commonly referred to as beet root.
Beta vulgaris (Beet Root) and Colon Health
Beet root represents another vegetable that contains multiple constituents that function to support intestinal health and prevent colon cancer via at least several known mechanisms. A sampling of the known medicinal constituents within beet include sugars [e.g., folate, saccharose, oligosaccharides, and polysaccharides (galactans, arabans, pectin)], fruit acids (e.g., L(-)-malic, D(+)-tartaric, oxaluric, adipic, citric, glycolic, and glutaric acids), amino acids (e.g., asparagine, glutamine), betaine (trimethylglycine) and triterpene saponins.(46)
In addition to beet root's actions in supporting colon/intestinal'health due to its folate and glutamine content, animal studies have shown dietary beet root fiber to reduce serum and liver lipids,(47-49) which are known risk factors in colon cancer.(50)
Beet and lipid metabolism
Sugar beet fiber fed to rats as 30% of a low fat diet for three weeks significantly decreased ileal apolipoprotein B mRNA expression that is responsible for LDL cholesterol synthesis.(51) As a possible consequence, fecal bile salt and cholesterol excretions were elevated. Beet fiber also significantly increased hepatic LDL receptor mRNA and lowered serum total and LDL cholesterol levels relative to cellulose and mushroom fiber (chitin) in rats.(52) The beet's demonstrated lipid lowering effect may be a result of the food's ability to increase the uptake of LDL cholesterol by the liver.
Protective properties of beet on the colon
Bobek et al.(53) examined the effect of red beet fiber on the development of alimentary hypercholesterolemia and dimethylhydrazine-induced carcinogenesis in the rat colon. The researchers showed that 15% red beet fiber in a hypercholesterolemic diet (0.3% dietary cholesterol) reduced serum cholesterol and triacylglycerol levels by 30% and 40%, respectively, and increased the fraction of HDL cholesterol. Of particular interest to researchers is the significant decrease in aortic cholesterol (nearly 30%).
Table 1
Lipids in serum, lipoproteins, and organs of rats fed a hypercholesterolemic diet with 5% cellulose, 15% cellulose, or 15% red beet fiber
| Parameter |
Diet |
| |
5% Cellulose |
15% Cellulose |
| N |
11 |
12 |
| Body weight (g) |
450 [+ or -] 16 |
455 [+ or -] 16 |
| Cholesterol |
| Serum (mmol/L) |
9.93 [+ or -] 0.22 |
9.19 [+ or -] 0.47 |
| VLDL (mmol/L) |
1.86 [+ or -] 0.13 |
1.61 [+ or -] 0.11 |
| %VLDL * |
19.2 [+ or -] 1.1 |
18.4 [+ or -] 1.1 |
| LDL (mmol/L) |
4.72 [+ or -] 0.43 |
3.93 [+ or -] 0.37 |
| %LDL * |
48.5 [+ or -] 1.9 |
45.1 [+ or -] 1.6 |
| HDL (mmol/L) |
3.14 [+ or -] 0.24 |
3.19 [+ or -] 0.25 |
| %HDL * |
32.3 [+ or -] 1.1 |
36.5 [+ or -] 1.3 |
| Liver (mmol/kg) |
511 [+ or -] 7 |
496 [+ or -] 13 |
| Heart (mmol/kg) |
10.06 [+ or -] 0.66 |
9.78 [+ or -] 0.66 |
| Aorta (mmol/kg) |
7.46 [+ or -] 0.33 |
7.23 [+ or -] 0.37 |
| Triacylglycerols |
| Serum (mmol/L) |
0.76 [+ or -] 0.03 |
0.67 [+ or -] 0.05 |
| Liver (mmol/L) |
48.6 [+ or -] 4.2 |
38.1 [+ or -] 5.82 |
| Heart (mmol/kg) |
1.54 [+ or -] 0.11 |
1.17 [+ or -] 0.15 |
| Parameter |
15% Red beet fiber |
| N |
11 |
| Body weight (g) |
471 [+ or -] 17 |
| Cholesterol |
| Serum (mmol/L) |
6 82 [+ or -] 0.53 (b, C) |
| VLDL (mmol/L) |
0.69 [+ or -] 0.07 (c, C) |
| %VLDL * |
10.6 [+ or -] 0.9 (c, C) |
| LDL (mmol/L) |
2.79 [+ or -] 0.36 (B) |
| %LDL * |
42.7 [+ or -] 2.0 |
| HDL (mmol/L) |
3.05 [+ or -] 0.43 |
| %HDL * |
46.7 [+ or -] 1.9 (C) |
| Liver (mmol/kg) |
523 [+ or -] 22 |
| Heart (mmol/kg) |
8.67 [+ or -] 0.49 |
| Aorta (mmol/kg) |
5.54 [+ or -] 0.34 (b, B) |
| Triacylglycerols |
| Serum (mmol/L) |
0.44 [+ or -] 0.03 (c, C) |
| Liver (mmol/L) |
45.1 [+ or -] 6.9 |
| Heart (mmol/kg) |
1.26 [+ or -] 0.18 |
* Fraction of total serum cholesterol
Statistically significant against 15% cellulose diet:
(a) p<0.05
(b) p<0.01
(c) p<0.001
Statistically significant against 5% cellulose diet:
(A) p<0.05
(B) p<0.01
(C) p<0.001
Red beet fiber caused a pronounced increase in the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase enzymes in colon, liver, and erythrocytes, supporting the hypothesis that oxidation pathways contribute to the disease state (data not shown), and illustrating that beet fiber likely promotes Phase II detoxification function in the intestine, blood, and liver. In addition, dietary red beet fiber reduced the incidence of precancerous lesions in the rat colon. Other animal studies support the finding that dietary beet fiber dose-dependently decreases serum and liver cholesterol levels and offers some protection against colon cancer.(54,55)
Final Thought
Given the complexity and overlapping roles of the intestinal tract, the immune system and the human detoxification system, it is unlikely that any single nutrient, such as folate, is wholly responsible for the effects that foods such as broccoli, cabbage and beets impart on the body's ability to'stave off colon cancer and maintain intestinal health.
© COPYRIGHT 2006 Dr. Gina L. Nick
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