"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 present valid scientific information available on the physiologic actions of known constituents and combinations of constituents, as they naturally occur in "functional foods," highlighting their medicinal and nutritive mechanisms of action in the body.

Chemoprevention and the Crucifers
The scientific community continues to recognize and validate the considerable relationship between vegetable intake and cancer. [1-3] Over 200 epidemiological studies show, with great consistency, that a low consumption of vegetables is directly associated with an increased risk of cancer (Table 1). Epidemiological studies also support the belief that dietary modification, through an increase in vegetable intake, could reduce the risk of cancer by 50% internationally. Specifically, researchers regard cruciferous vegetables, and particularly those that are members of the Brassica plant family, as critical elements in the risk reduction associated with vegetable intake and cancer. [4-8] Further, in people under 55 years of age, cruciferous vegetable intake is inversely correlated with colon cancer incidence and comparatively among smokers the chemoprotective benefits of Brassica consumption are even greater. [9,10] Van Poppel et al. [11] examined 6 cohort studies and 74 case control studies that supported an in verse correlation between Brassica consumption and cancer risk. The association was found to be most consistent for lung, stomach, colon, and rectal cancers, and least consistent for prostatic, endometrial, and ovarian cancers. In studies examining total vegetable consumption an inverse association with cancer risk is also found, with the Brassicas showing the strongest effects as a subgroup.[12] Brassicas also are low in fat, low in calories, and are potent sources of vitamins, minerals, fiber, and phytochemicals, all of which have been linked to cancer prevention. [13-15]

Table 1
Review of epidemiological studies demonstrating the relationship between vegetable consumption and cancer protection.[16]

Cancer Site	Relative percentage of studies demonstrating cancer protection with high vegetable intake	Relative Median Risk Low vs. high consumption of vegetables
Hormone-related Breast	57%	1.3
Ovary/endometrium	75%	1.8
Prostate	100%	1.3
Epithelial Oral	100%	2.0
Lung	96%	2.2
Larynx	100%	2.3
Esophagus	93%	2.0
Stomach	89%	2.5
Pancreas	82%	2.8
Cervix	88%	2.0
Bladder	60%	2.1
Colorectal	57%	1.9
Miscellaneous	75%	-
Total	75%

A discussion of the biochemical and physiologic implications of increasing one's intake of cruciferous vegetables will follow. The term "chemoprevention," for the purpose of this research article, refers to the strategic approach of decreasing one's susceptibility to carcinogenic factors through the administration of dietary chemicals, as introduced to the body within the matrix from which they originated (i.e., ingesting the whole vegetable vs. an isolated fraction). The rationale behind emphasizing the use of whole vegetables as opposed to an isolated fraction (considered a chemoprotective agent) is that the degree to which the protective effect of vegetables can be attributed to the nutritional or tertiary components, and to what extent indirect effects such as an equivalent reduction in fat consumption and associated increase in vitamin, fiber and carotenoid intake may be responsible for the protective effect, is not well defined. Nonetheless, the dietary approach of increasing one's intake of cruciferous vegetables to defend oneself from cancer-causing agents has become widely recognized in the medical research community as a realistic and rational practice in the war against cancer. [17]

Medicinal Properties in Whole Foods

Phase II Enzyme Inducers
Exposure to cruciferous vegetables (e.g., kale, Brussels sprouts, Chinese cabbage, bok choy, cabbage, turnips, collards, kohlrabi, rutabaga, cauliflower and broccoli) causes a coordinated metabolic induction of many of the Phase II liver detoxification enzymes that detoxify carcinogenic (cancer-causing) compounds from the body, thus reducing the susceptibility of cells to these substances. Glutathione transferases, NAD(P)H, quinone oxidoreductase, glucuronosyltransferase, and epoxide hydrolase are all Phase II enzymes that inactivate carcinogens.

Mechanisms of action of Phase II enzyme inducers
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. Interestingly, the medicinal properties of glucosinolates are noted in the writings of Pythagoras and Hippocrates and at least 20 different compounds were identified by the 1980s. [18] All cruciferous vegetables are believed to contain glucosinolates, but Brussels sprouts and broccoli have some of the highest levels.
The glucosinolates found in whole foods 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.

S-[beta]-D-[C.sub.6] [H.sub.11] [O.sub.5] [Myrosinase.sub.[right arrow]]R-N=C=S + [HSO.sub.4] - N-O-[SO.sub.3]
Glucosinolate
Isothiocyanate

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 lung, colon, stomach, liver, and breast cancers. [19] 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. [20] Organosulfur compounds such as dithiolethiones that are found in cruciferous vegetables are also considered putative chemopreventive agents via their effect on Phase II detoxification enzymes. [21, 22]

Glucosinolates commonly found in cruciferous vegetables
The most common glucosinolate compounds found in cruciferous vegetables, and more frequently in Brassica vegetables, are alkylthioalkyl glucosinolates, indole glucosinolates, and [beta]-hydroxyalkenyl glucosinolates. The [beta]-hydroxyalkenyl glucosinolates such as progoitrin give rise to oxazolidine-2-thione goitrin, which is a potent goitrogen, inhibiting iodine incorporation and thyroxin formation. Hence, over-consumption of Brassica vegetables such as kale and cabbage can cause goiter in animals and in humans. [23] However, broccoli does not contain significant quantities of these compounds.

Indole glucosinolates, including glucobrassicin, 4-hydroxyglucobrassicin, 1-hydroxyglucobrassicin, neo-glucobrassicin, and 4-methoxyglucobrassicin, form unstable isothiocyanates when hydrolyzed by myrosinase. This reaction gives rise to compounds such as 3,3'-diindolylmethane, indole-3-acetonitrile and indole-3-carbinol. These compounds only represent weak inducers of Phase II detoxification enzymes, although as documented in most in-vivo studies with indole-3-carbinol, there is a reported chemoprotective role for this compound. [24,25] It is important to note, however, that metabolic derivatives of indole glucosinolates also induce select cytochrome P-450 enzymes that can result in the formation of procarcinogens. The picture is not perfectly clear here, but what is known is that these derivatives simultaneously function as inducers of Phase I and Phase II enzymes.

The alkylthioalkyl glucosinolates, such as glucoraphanin, glucoiberin and glucoerucin, form the isothiocyanates sulforaphane, iberin and erucin. These compounds are significant inducers of the Phase II detoxification enzymes, and they do not induce Phase I detoxification enzymes, as do the indole glucosinolates. [26]

In summary, glucosinolates, which are not considered biologically active components in and of themselves, are the key compounds responsible for phase II enzyme induction activity in cruciferous vegetables. The glucosinolates must undergo hydrolysis to isothiocyanates in order to demonstrate Phase II induction activity. Interestingly, the relative degree of potency of Phase II enzyme inducers is dependent upon multiple factors including cultivation techniques, handling and storage practices, and methods of food preparation that are independent of the relative concentration of glucosinolate compounds found in the sample. [27] Also, with regard to Brassicas, there appears to be no net synthesis of Phase II inducers after sprouting and their concentration decreases as the plant grows. [28] As a result, Brassica sprouts may contain 10-100 times the Phase II induction activity of mature plants. Indeed, extracts of broccoli sprouts have been shown to be more efficient at inhibiting rat tumorigenesis than extracts o f mature plants. [29] Conversely, mature broccoli contains significant amounts of indole compounds not found in sprouts that induce both Phase I and II detoxification enzymes. [30] Glucosinolates are water-soluble, and hence it would be advisable to employ cooking techniques (such as steaming, stir frying, and rapid boiling with minimal water) to prevent excessive leaching of the isothiocyanate compounds.

Research

Crucifers and liver detoxification
Staack et al. [31] examined the effects of a mixture of glucosinolate breakdown products from Brussels sprouts on the induction of liver detoxification enzymes in rats. The mixture (full strength, 60%, and 20%) elevated levels of cytochrome P450 1A (CYP1A), glutathione-S-transferase (GST), quinone reductase (QR), glutathione reductase (GR), and glutathione (GSH) in a dose dependant manner, supporting the hypothesis that glucosinolates found in green vegetables are important in the regulation of hepatic detoxification (Table 2).

Table 2
Dose-dependent induction of Phase II detoxification molecules in response to ingestion of a mixture of Brussels sprout glucosinolate breakdown products.[32]

Treatment	CYP lAa	GSTb
Undiluted Mixture
100% mix	1378.0[+ or -]54.1 *	1343.4[+ or -]79.8 *
Control	124.2[+ or -]7.3	541.0[+ or -]41.4
Pair-fed	84.8[+ or -]7.8	511.0[+ or -]35.9
Diluted Mixture
60% mix	606.8[+ or -]47.1 *	728.5[+ or -]52.5 *
20% mix	211.5[+ or -]22.4 *	499.0[+ or -]34.0 *
Control	60.9[+ or -]6.0	369.5[+ or -]32.0
Pair-fed	50.2[+ or -]3.9	421.2[+ or -]37.1
Treatment	Qrc	Grd
Undiluted Mixture
100% mix	185.9[+ or -]10.8 *	54.3[+ or -]3.22 *
Control	30.0[+ or -]2.4	30.6[+ or -]0.85
Pair-fed	32.5[+ or -]4.8	28.2[+ or -]1.51
Diluted Mixture
60% mix	168.7[+ or -]21.1 *	44.8[+ or -]2.2 *
20% mix	109.2[+ or -]8.4 *	37.5[+ or -]0.86 *
Control	70.7[+ or -]12.0	30.6[+ or -]0.88
Pair-fed	49.7[+ or -]5.7	30.4[+ or -]0.86
Treatment	GSHe
Undiluted Mixture
100% mix	5.53[+ or -]0.16
Control	2.71[+ or -]0.12
Pair-fed	2.77[+ or -]0.06
Diluted Mixture
60% mix	2.82[+ or -]1.06
20% mix	2.46[+ or -]0,30
Control	3.24[+ or -]0.44
Pair-fed	3.36[+ or -]0.32

In addition to an antioxidant-free diet, rats were fed the glucosinolate mixture by gavage 12 hours after daily feeding.
(a) Ethoxyresorufin dealkylation (pmol/min/mg microsomal protein)
(b) CDNB conjugate formation (nm/min/mg cytosolic protein)
(c) DCPP reduced (nm/min/mg cytosolic protein)
(d) NADPH oxidized (nm/min/mg cytosolic protein)
(e) GSH ([micro]mol/gm liver weight) (*) Significantly different from control (p[less than]0.05)

The following Brussels sprout glucosinolate breakdown products and amounts were used in the mixture fed to the rats:

• Indole-3-carbinol (I3C; 56 mg/kg)
• Iberin (38 mg/kg)
• Phenylethylisothiocyanate (PEITC; 0.1 mg/kg)
• Cyanohydroxybutene (crambene; 50 mg/kg)

The amounts reflect the proportionate amounts of each glucosinolate compound found in Brussels sprouts standardized to 50 mg crambene/kg (induces glutathione without toxic effects).

It is important to note that in this study the individual glucosinolate breakdown products were also tested. While indole-3-carbinol (I3C) was the only glucosinolate in the mixture to significantly increase enzyme activity, the glucosinolate mixture containing I3C was considerably more effective, supporting a synergistic mechanism of action between the compounds. This suggests that bioactive molecules ingested as part of a complete nutritional regimen may be considerably more effective than the isolated active principles used alone.

Preliminary data suggest that a commercially available complex of vacuum dried organic alfalfa, buckwheat, Brussels sprouts, barley grass, and kale induces significant increases in quinone reductase activity in both human and mouse hepatoma cell lines (Dr. Elizabeth Jeffery, University of Illinois-Urbana/Champagne, personal communication).

Isothiocyanates have also been shown to act as anticarcinogens by inducing detoxification of environmental mutagens. [33] Sulforaphane blocked 7,12-dimethylbenz(a)-anthracene-induced mammary tumors in rats [34] and broccoli extract was a potent inducer of detoxification enzymes in a mouse hepatoma cell assay, probably due to sulforaphane as well. [35]

Fifty percent of people completely lack the glutathione-S-transferase Ml (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. [36] 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 and kale, but not cabbage, cauliflower, or Brussels sprouts, were significantly associated with 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 di d correlate with 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. However, neither urinary nor serum isothiocyanate measurements were taken in the subjects, so other mechanisms cannot be ruled out. It is clear from the body of research available that consumption of higher levels of cruciferous vegetables is indicated for reducing the risk of some cancers.

Crucifers and cancer
Verhoeven et al. [37] examined the results of seven cohort studies and 87 case-control studies on the association between Brassica vegetable consumption and cancer risk. In five of the cohort studies, Brassica consumption correlated inversely with the risk of certain cancers. The specific findings are summarized in Table 3.

Table 3
Prospective cohort studies showing a significant inverse relationship between consumption of Brassica vegetables and cancer risk (five studies out of seven).[37]

Reference	Study population		Follow-up
Kvale et al. (1993)	13,785 men and 2,928 women in Norway		11.5 years (113 cancer cases)
Colditz et al. (1985)	1,271 elderly people in Massachusetts		5 years (42 cancer cases)
Chyou et al. (1990)	8,006 men of Japanese ancestry in Hawaii		18 years (111 cancer cases)
Steinmetz et al. (1993)	41,837 poatmenopausal women in Iowa		4 years (138 cancer cases)
Day et al. (1994)	1,090 oral and pharyngeal cancer patients In the US		5 years (80 cases 01 second primary cancer)
Reference	Cancer type	Brassica vegetable	Variables adjusted for
Kvale et al. (1993)	Lung	Cabbage, cauliflower and rutabaga	Age, smoking, region, urban/rural
Colditz et al. (1985)	All types	Broccoli	Age
Chyou et al. (1990)	Stomach	All Brassicas	Age, current smoking status
Steinmetz et al. (1993)	Lung	Broccoli	Age, energy intake, smoking
Day et al. (1994)	Varied	Cabbage, broccoli, Brussels sprouts, and coleslaw	Age, index tumor stage, smoking, drinking, energy intake

Of the 87 case-control studies, 68 (78%) found a lower cancer risk associated with consumption of Brassica vegetables, although not all were significant and some applied to only one sex. The number of case-control studies in which at least one significant inverse relationship between Brassicas and cancer risk was found is shown in Table 4.

Table 4
Case-control studies showing a significant relationship between cancer risk and consumption of Brassica vegetables by cancer type (positive and negative correlations).[37]

Cancer type	Total Number of Studies	Number of studies showing a significant Inverse association
Colon	15	6 (40%)
Stomach	11	5 (45%)
Rectum	10	4 (40%)
Lung	9	6 (67%)
Cancer type	Number of studies showing a significant positive association
Colon	0
Stomach	1 (9%)
Rectum	0
Lung	0

Although the percentage of case-control studies showing a significant inverse relationship between Brassica consumption and cancer risk is less than half in most cases, bear in mind that other variables known and unknown undoubtedly play a role in the relationship. Furthermore, only one study showed a positive correlation, suggesting that the inverse relationship between Brassica consumption and cancer is real and not simply an artifact of chance.

Because DNA damage is considered a pathogenic event in the initiation of many cancers, [38] the urinary excretion of biomarkers of DNA damage serves as a potential indicator of cancer risk. An abundant and potentially mutagenic lesion caused by oxidative DNA damage is the incorporation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) adducts into the DNA strand. [39] Normal DNA repair mechanisms excise 8-oxodG, which is excreted unchanged and independent of diet in the urine. Thus, the relative rate of excretion represents the integrated rate of oxidative DNA damage in the body.

Verhagen's group [39] investigated the hypothesis that dietary cruciferous vegetables result in a reduction of oxidative DNA damage in healthy, male, non-smoking humans. Ten volunteers consumed a diet containing 300 g of cooked, non-cruciferous vegetables (endive, French beans, peas, beets, fava beans, chicory and assorted other legumes and vegetables) per meal during a three-week run-in period. During the subsequent three-week intervention period, five of the volunteers continued on this diet (control group) while five others began consuming 300 g of cooked Brussels sprouts at the expense of 300 g of a glucosinolate-free vegetable. 24-hour urine samples were collected at the end of the run-in and intervention periods. The Brussels sprouts caused no adverse effects as measured by several clinico-chemical parameters for liver, renal, thyroid, and blood-coagulation functions. During the run-in period, there was no difference in 8-oxodG excretions between the sprouts and cruciferous vegetable-free groups. Withi n the control group, there was no significant change in excretion between the runin and the intervention period. By contrast, the 8-oxodG excretion decreased by 28% in the Brussels sprouts group during the intervention period.

Overview
These clinical results coupled with the results of earlier trials strongly suggest that cruciferous vegetables:

• Detoxify by upregulating detoxification enzymes
• Prevent oxidative cell and DNA damage
• Are chemoprotective against numerous types of cancer

© COPYRIGHT 2006 Dr. Gina L. Nick

References

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