Glucosinolates: The Phytochemicals of Nutraceutical Importance

Volume 9, Issue 1 2012 Article 13

Journal of Complementary andIntegrative Medicine

Glucosinolates: The Phytochemicals ofNutraceutical Importance

Dhan Prakash, Amity Institute for Herbal Research &Studies, Amity University-UP

Charu Gupta, Amity Institute for Herbal Research &Studies, Amity University-UP

Recommended Citation:Prakash, Dhan and Gupta, Charu (2012) "Glucosinolates: The Phytochemicals of NutraceuticalImportance," Journal of Complementary and Integrative Medicine: Vol. 9: Iss. 1, Article 13.DOI: 10.1515/1553-3840.13

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Glucosinolates: The Phytochemicals ofNutraceutical Importance

Dhan Prakash and Charu Gupta

AbstractGlucosinolates (thioglucoside-N-hydroxysulphates) constitute a homogeneous class of

naturally occurring thiosaccharidic compounds mainly found in the botanical order Brassicales.They can be hydrolyzed by myrosinase to produce D-glucose and various other degradationproducts like isothiocyanates (ITCs)-depending on the aglycon part. The exact function ofglucosinolates (GLSs) in the plant is unclear, however their potent odour and taste suggests a rolein herbivore and microbial defense. They are known for their fungicidal, bacteriocidal, nematocidaland allelopathic properties and have recently attracted intense research interest because of theircancer chemo-protective attributes. Iso-thiocyanates, one of the hydrolyzed products, show bestanti-carcinogenic activity.

KEYWORDS: phytochemicals, nutraceuticals, glucosinolates, isothiocyanates, ascorbigen,methyl-ascorbigen

Author Notes: Corresponding Author: Prof. Dr. Dhan Prakash, E-mail: [email protected] Institute for Herbal Research & Studies, Amity University UP, Sector-125, Noida-201303,UP, India Acknowledgements: Authors are grateful to Dr Ashok K Chauhan, Founder President andMr Atul Chauhan, Chancellor, Amity University UP, Noida-201303, (India) for the encouragement,research facilities and financial support.


Introduction Foods having chemo-preventive properties have attracted a lot of interest amongst common man. Most of the drugs contain the bioactive chemicals originally discovered in plant foods. Epidemiological evidence show that consumption of cruciferous vegetables can significantly reduce the risks of a number of tumors and cancers (Lampe and Peterson 2002, Vallejo et al. 2002, 2003A, B, C; Jones et al. 2006, Oerlemans et al. 2006). The edible plant within the Brassica genus (family Brassicaceae) contains an important health-promoting group of compounds known as glucosinolates (GLSs). Its various metabolites like iso-thiocyanates (ITCs), show anti-carcinogenic action and these phytochemicals, in concert with other constituents such as flavonoids, vitamins and mineral nutrients, could be the major efficacious agents (Barillari, et al. 2005, Hintze et al. 2005). GLSs constitute a well-defined group of secondary plant metabolites in cruciferous plants. They undergo hydrolysis, catalyzed by an endogenous plant enzyme, known as myrosinase, into a range of biological active compounds (Bones and Rossiter 2006, Cartea et al. 2008). The unique properties of GLSs and ITCs or mustard oils was first reported at the beginning of the 17th century in an effort to understand the chemical origin of the sharp taste of mustard seeds. Earlier researches have highlighted the negative aspects of these compounds because of the prevalence of certain anti-nutritional or goitrogenic GLSs in the protein-rich defatted seed meals from widely grown oilseed crops and in some domesticated vegetable crops. There is, however, an opposite and positive side of this picture represented by the therapeutic and prophylactic properties of GLSs as nutritional or functional properties. Till date more than 120 GLSs have been characterized and their potent odour and taste suggests a role in herbivore and microbial defense. GLSs and their breakdown products are now known for their fungicidal, bacteriocidal, nematocidal and allelopathic properties. They are a major constituent of folk medicines and have recently attracted intense research interest because of their cancer chemoprotective attributes (Fahey et al. 2001, Anilakumar et al.2006). Occurrence GLSs are exclusively found in dicotyledonous plants (Table 1), although closely related taxonomic groups contain only a small number of such compounds. Family Brassicaceae (syn. Cruciferae; including Brassica spp and Raphanus spp) alone contains more than 350 genera and 3000 species (Fahey et al. 2001, 2002). Among the Brassicaceae, the genus Brassica contains a large number of the commonly consumed species. Many commonly consumed vegetables, condiments, forages and oil containing plants, such as cabbage, broccoli,

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Prakash and Gupta: Glucosinolates: The Phytochemicals of Nutraceutical Importance

Published by De Gruyter, 2012


cauliflower, collards, kale, mustard, brussels sprouts and rapeseeds are good source of GLSs (Song et al. 2005, Oerlemans et al. 2006). Broccoli derived from a species of wild cabbage, Brassica oleracea is consumed widely in Europe (Margen 2002). These vegetables are an excellent dietary source of phytochemicals including GLSs and its breakdown products, phenolics and other antioxidants like vitamins C and K1, as well as dietary essential minerals like Ca, Mg, Na, K, Fe, Zn, etc. (Finley et al. 2001, Jeffery et al. 2009). Hundreds of cruciferous species investigated, are able to synthesize GLSs. However, GLSs are by no means confined to crucifers; at least 500 species of non-cruciferous dicotyledonous angiosperms have been reported to contain one or more of the over 120 known GLSs. Some of the important sources of GLSs are Arabis hirsute Table 1: Important plant families of GLS-containing angiosperms (Fahey et al. 2001) Family Chemical class Glucosinolates Brassicaceae

Sulphur in side chain, Olefins, Alcohols, Ketones, Aromatic, Benzoates, Indole, Aliphatic straight and branch chain, Multiple Glycosylates

Sinigrin, Glucobrassicanapin, Glucopangulin, Glucoalyssin, Glucoerucin

Capparaceae

Sulphur containing side chain, Alcohols, Ketones, Aromatic, Indole Olefins, Aliphatic straight and branch chain.

Glucocappasalin, Glucoiberin, Gluconapin

Caricaceae Aromatic Glucotropaeolin Limnanthaceae Aliphatic alcohols, Aromatic Glucolimnanthin Moringaceae

Olefins, Aliphatic alcohols, Aromatic, Multiply glycosylates

Glucosisymbrin

Phytolaccaceae Olefins, Aliphatic alcohols, Aromatic

Glucolepigramin

Resedaceae

Aliphatic alcohols, Aromatic, Indole, Multiply glycosylates

Gluconasturtiin

Salvadoraceae Olefins, Aromatic Glucoputranjivin Tovariaceae Olefins Neoglucobrassicin Tropaeolaceae Aliphatic straight chain, Olefins

,Aliphatic alcohols, Aromatic Glucoaubrietin

Barbarea praecox, B. vulgaris, Brassica campestris, B. juncea, B. napus, B. nigra, B. oleracea var. botrytis subvar. cymosa, Conringia orientalis, Isatis tinctoria, Lepidium sativum, Nasturtium officinalis, Reseda luteola, Reseda alba,

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Journal of Complementary and Integrative Medicine, Vol. 9 [2012], Iss. 1, Art. 13


Sibara virginica and Tropaeolum majus (Fahey et al. 2001, 2002). Most GLS-containing genera are clustered within the Brassicaceae, Capparaceae and Caricaceae, these include the largest number of GLS-containing species (Table 1). Structure GLSs are β-thioglucoside N-hydroxysulphates [also known as (Z)-(or cis)-N-hydroximinosulphate esters or S-glucopyranosyl thiohydroximates], with a side chain (R) and a sulphur-linked β -D-glucopyranose moiety. A thioglycosylated sulphated oxime is an important structural feature of all known GLSs, which are mainly distinguished by variations in the amino acid derived carbon skeleton known as the ‘side chain’ (Mithen et al. 2000, Rungapamestry et al. 2007). GLSs share a similar basic structure consisting of a D-thioglucose group, a sulphonated oxime group and a side chain derived from methionine, phenylalanine, tryptophan or branched-chain amino acids (Figure 1).

Figure 1: General structure of glucosinolate

Maximum GLSs contain either straight or branched carbon chains. Many of these compounds also contain double bonds (olefins), hydroxyl or carbonyl groups, or sulphur linkages in various oxidation states. The largest single group (one-third of all GLSs) contains a sulphur atom in various states of oxidation (e.g. methyl thioalkyl-, methyl-sulfnyl-alkyl-, or methyl-sulfonyl-alkyl). Another small group of benzyl GLSs has an additional sugar moiety like rhamnose or arabinose, in glycosidic linkage to the aromatic ring. The presence of these sugars is of unknown significance; although it is intriguing that they are present in two families of plants (the Moringaceae and Resedaceae) containing certain genera that are widely exploited for their pharmacological properties. Additionally, a number of sinapoyl and cinnamoyl salts and esters of some of the common GLSs are substituted on the thioglucoside moiety (Fahey et al. 2001, 2002, West et al. 2004).

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Classification GLSs have been classified according to their structure as aliphatic, aromatic, α-methylthioalkyl and heterocyclic e.g., indole (Fahey et al. 2001, Cartea et al. 2008). There are following seven major classes of GLSs:

Methylsulphnylalkyl GLSs (glucoiberin, glucoraphanin and glycoalyssin) Olefenic GLSs (sinigrin, gluconapin and progoitrin) Aromatic GLSs (gluconasturtiin). Ketonic GLSs (glucocappasalin, glucopangulin) Alcoholic GLSs (gluconapoleiferin, progoitrin, epiprogoitrin) ω-Hydroxyalkyl (Benzoates) GLSs (glucomalcomiin,

glucobenzosisymbrin) Heterocyclic (Indole) GLSs (glucobrassicin, neoglucobrassicin)

Hydrolyzed Products Hydrolysis of GLSs is catalyzed by an endogenous plant enzyme, known as myrosinase (thioglucohydrolase; E.C. 3.2.1.147). A wide range of biological active breakdown products like nitriles, ITCs, thiocyanates, epithionitriles and vinyl oxazolidinethiones are produced. Some compounds, for example ITCs, indoles, thiocyanates, or nitriles, showed anti-carcinogenic activity by inducing phase II biotransformation enzyme activity (Rungapamestry et al. 2006).

Early studies reported that myrosinase is localized in the cytoplasm of specialized plant cells, myrosin cells. GLSs and myrosinase are segregated in intact plants (Brandt 2004, Sarikamis et al. 2009). Autolysis or tissue damage during freezing and thawing, chopping, chewing brings myrosinase in contact with GLSs and hydrolysis occurs (Rungapamestry et al. 2007). The products of hydrolysis have important roles in the plant defense system against insect, fungi and microorganism infections. Similarly animals consuming plants, GLSs are not bioactive until they have been hydrolyzed to an associated ITC (Rouzaud et al. 2003) by myrosinase enzyme. The latter is released by disruption of the plant cell through harvesting, processing, or mastication as mentioned earlier (Finley 2005). Myrosinase activity results in the release of the glucose moiety leaving behind an unstable intermediate which spontaneously rearranges to produce several products (Mithen et al. 2000, Oerlemans et al. 2006). The type of product formed depends on several factors, such as pH, substrate or availability of ferrous ions (Kristal and Lampe 2002, Lund 2003, Guerrera 2005, Shapiro et al. 2006).

Several ITCs produced in hydrolysis and through rearrangement of GLSs are nutritionally important products (Song et al. 2007).The decreased risk of cancer linked to a diet rich in Brassica vegetables is widely associated to ITCs absorbed following ingestion of GLSs. ITC reacts with free amino and sulphydryl

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groups of various proteins. These products are also responsible for the characteristic flavour and odour of Brassica vegetables (Das et al. 2000) and for the biting taste of important condiments such as horseradish and mustard. Sinigrin and progoitrin, important GLSs are related to bitterness in Brussels sprouts (Traka et al. 2009), while in cooked cauliflower sinigrin and neoglucobrassicin were responsible for the bitter taste. The characteristic odour and taste of radish is due to the formation of 4-methylthio-3-butenyl ITC-derived GLSs. (Engel et al. 2002, Anilakumar et al. 2006, Volden et al. 2008)

The breakdown products of indolylmethyl GLSs consisted of indole-3-acetonitrile, indole-3-carbinol (I-3-C) and 3, 3’-diindoylmethane. Progoitrin, a major component of cabbage, cauliflower, brussel sprouts and kale has anti-thyroidal property because of its two reactive metabolites progoitrin ITC (2-hydroxy-3-butenyl) and goitrin (5-vinyloxazolidine-2-thione). Latter is produced from the former in cyclization reaction (Anilakumar et al. 2006, Vandermeiren et al. 2009).

A great deal of research has been focused on sulforaphane [1-isothiocyanato-C (methylsulfinyl)-butane], which has been identified in broccoli as a product of enzymatic or acid hydrolysis of the corresponding ω-(methylsulfinyl)-alkyl-GLS (glucoraphanin), (Rungapamestry et al. 2007). Sulforaphane reduces the incidence of a number of forms of tumour in various experimental models and cell cultures. The chemoprotective effect of sulforaphane was thought to be due solely to its ability to behave as a mono-functional inducer of phase II enzymes, which are known to represent the most important group of de-toxication enzymes of the human organism. Recently, however, sulforaphane has also been shown to inhibit the CYP2EI iso-enzyme of the cytochrome P450, thus emerging as an inhibitor of phase I enzymes. Natural bioactives, GLSs breakdown products in broccoli like I-3-C, benzyl ITC and phentyl ITC, may also be responsible for selective induction of apoptosis in cancer cells (Kristal and Lampe 2002, Jackson and Singletary 2004, Finley et al. 2005, Bialecki et al. 2010).

Myrosinase It has been purified and characterized from several sources, including white mustard (Sinapis alba), cress (Lepidium sativum), yellow mustard (Brassica juncea), rapeseed (Brassica napus) and wasabi (Wasabia japonica). Myrosinases are activated to various degrees by ascorbic acid and in some instances the enzyme is almost inactive in its absence. It has been suggested that ascorbate provides a nucleophilic catalytic group and activation is not dependent on the redox reactivity of ascorbate. Early work had shown that ascorbate creates an

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allosteric effect on the activity of the enzyme. Subsequently it was shown that ascorbate acts as a catalytic base.

Evidence strongly suggests that upon ingestion by humans, β-thioglucosidase activity of gut microflora is largely responsible for converting ingested GLSs to ITCs. Similar observations have also been made in numerous animal studies. After hydrolytic cleavage of the β-glucosyl moiety, the sulfate moiety is released non-enzymatically to form the thiohydroxamate-O-sulfonate from both aliphatic and aromatic GLSs. This unstable intermediate then rearranges to form ITCs, or other breakdown products (e.g. thiocyanates, nitriles, epithionitriles, oxazolidine-2- thiones) in a manner that depends upon the GLS substrate as well as the reaction conditions like pH, or the presence of Fe2+ or epithiospecifier protein (Burmeister et al. 2000, Volden et al. 2008, Traka et al. 2009).

Ascorbigens Some indole products of GLS are claimed to demonstrate breast cancer-preventing actions, due to their affinity and ability to bind with estrogen receptors. Such an activity has been displayed by 3,3’-diindolylmethane, I-3-C and indolo[3,2-b] carbazole, which is formed from ascorbigen (ASC) or I-3-C in a strongly acidic environment upon the activity of gastric juice (Horn et al. 2002; Traka et al. 2009). ASC is a natural derivative of L-ascorbic acid (AA) and was identified as a biotransformation product of the alkaloid glucobrassicin. ASC can

O

OH OHO

OH

H2COH

NH

N

CH3

O

OH OHO

OH

OH H2C

Ascorbigen 1’ Methyl Ascorbigen

Figure 2: Chemical structure of ascorbigen (ASC) and 1'-methylascorbigen (MeASC)

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be isolated from some fresh, non-fresh or sour cruciferous vegetable tissues (cabbage, kohlrabi, savoy cabbage, etc.). Their biological evaluation showed that the most active substance is 1'-methylascorbigen (MeASC) that inhibits tumor growth in animals, protects animals from some bacterial and viral infections and also has an immuno-modulating activity. MeASC (Figure 2) has a pronounced apoptotic effect in which formaldehyde from the methyl group of MeASC plays a crucial role (Moldrup et al. 2011). Biological Activity GLSs are a highly diverse and variable group of phytochemicals. Studies show that they cause an increase in the activities of biotransformation enzymes in various tissues (Anilakumar et al. 2006, Halkier and Gershenzon 2006, Kosh et al. 2011). The antioxidant enzymes like glutathione peroxidases (GSH-Px), glutathione reductase (GSSGR), glutathione S-transferase (GST) and superoxide dismutase (SOD) play an important role in cellular oxidative stress. It was noted that I-3-C at normal dietary levels does not induce the oxidative enzymes. However in mice fed on semi-purified diets containing I-3-C causes significant increase in both hepatic and intestinal GST. I-3-C was found to reduce GSSGR and induce GSH-Px and SOD in rat liver. Glucoraphanin also induced hepatic quinone reductase (QR) and GST in mice (Guerrera 2005, Anilakumar et al. 2006).

Anti-carcinogenic Activities In recent years, cancer prevention by natural products has received considerable attention. The potential protective role of Brassica vegetables and bioactive phytochemicals of these vegetables, such as flavonoids (e.g. quercetin), minerals (e.g. selenium) and vitamins (e.g. Vitamin C) are well established. ITCs and I-3-C, has been extensively studied and shown chemo-protective activities during initiation and promotion phases of cancer development (Cartea et al. 2008, Jeffery et al. 2009). Results clearly point towards a positive correlation between cancer prevention of many target organs and consumption of Brassica vegetable or their bioactive phytochemicals. The epidemiological literature also support for the hypothesis that high intakes of Brassica vegetables reduce prostate, lung and gastrointestinal tract cancer risk. There are clear indications that they block tumor initiation by modulating the activities of Phase I and Phase II biotransformation enzymes and suppress tumors by apoptosis (Moldrup et al. 2011). In vitro and in vivo studies have reported that ITCs affect many steps of cancer development, including modulation of phases I and II detoxification enzymes. They function as a direct or indirect antioxidant by phase II enzyme induction thus modulating cell

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signaling, induction of apoptosis, control of the cell cycle and reduction of Helicobacter infections. The most characterized GLSs compounds are sulphoraphane, phenethyl ITC, allyl ITC and I-3-C, but many other ITCs that are present in lower quantities may also contribute to the anti-carcinogenic properties of Brassicaceae (Song et al. 2007). Various cited examples of dietary anticancer bioactives from broccoli include anti-proliferative effects of sulphoraphane in human breast cancer (Jackson and Singletary 2004, Brandi et al. 2005) reduced risk of cancer via decreased damage to DNA (Gill et al. 2004, Jeffery et al. 2009) effects on the regulation of intestinal cell growth and death in colon cancer (Parnaud et al. 2004), as well as the cancer-protective effect of high-selenium broccoli (Shapiro et al. 2006) or the exertion of a protective effect in prostatic tumours (Giovannucci et al. 2003, Canene-Adams et al. 2005). For example sulphoraphane induced apoptosis in prostate cancer cells is initiated by reactive oxygen species generation and the fact that both intrinsic and extrinsic caspase cascades contribute to the cell death caused by this highly promising cancer chemo-preventive agent (Singh et al. 2005). Additional effects of bioactives like ITCs from broccoli on bladder carcinoma cells (Munday and Munday, 2002, Tang and Zhang 2004), on antioxidant capacity and on cellular oxidative stress, as well as cholesterol lowering effects (Suido et al. 2003) and protective effects on cardiovascular disease (Sesso et al. 2003) and Helicobacter pylori infections (Galan et al. 2004), supports the fact that the dose level of bioactives may be effective through human consumption of Brassica vegetables. So this could contribute to the lower incidence of different types of cancer and diseases in individuals who regularly consume such vegetables. Unfortunately, the biological activity of these molecules is compromised by the removal of the sulphate. After desulphation, they can no longer serve, as substrates for myrosinase and thus their cognate ITCs are not available for bioassay or for direct measurement by cyclo-condensation-key tools in the study of the pharmacokinetics, pharmaco-dynamics and bioactivity of these compounds.

Selenium (Se) is a nutritionally essential element and Se deficiency results in disease conditions in humans and domestic livestock (Raskin et al. 2002). There are evidences that Se intake offer protection against cancer (Combs et al. 2001). Se-methylated amino acids such as Se-methyl selenocysteine (SeMSC) are metabolized primarily in the excretory pathway, and data suggests that methyl selenol generated in this pathway is the metabolite, which is most responsible for preventing cancer (Cartea et al. 2008). Broccoli accumulates Se in methylated forms and many other Brassicaceae species also accumulate Se (Finley 2005). It has been reported that I-3-C has an inhibitory effect on cell growth in human cervical and endometrial cancer cells (Chinni et al. 2001, Anilakumar et al. 2006). It was shown that the ITC metabolite of sulphorane was a major inducer of

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quinone reductase (QR) and phenylethyl isothiocynate (PEIT), a hydrolyzed product of gluconasturtiin was effective against nitrosamine-induced raise in oesophageal cancer (Traka et al. 2009).

Little is known about the direct effect of broccoli sprouts on human health, even though in vitro and in vivo data provided evidence that supports the belief that young cruciferous sprouts with their high concentrations of phytochemicals may be a potent source of protective chemicals against cancer (Gill et al. 2004). Recently, a phase I study of multiple biomarkers for metabolism and oxidative stress after 1-week intake of broccoli sprouts was carried out and it revealed that only one week of broccoli sprouts intake improved cholesterol metabolism and decreased oxidative stress markers (Murashima et al. 2004). Broccoli sprouts are a rich source of GLSs and ITCs that induce phase II detoxication enzymes, boost antioxidant status and protect animals against chemically induced cancer. The ITCs are about six times more bio-available than GLSs, which must first be hydrolyzed. Thorough chewing of fresh sprouts exposes the GLSs to plant myrosinase and significantly increases dithiocarbamate excretion.

The anti-carcinogenic properties of cruciferous vegetables have been attributed to I-3-C content while the protective effect has been attributed to induction of enzymes such as cytochrome P-450. A high urinary excretion of ITCs from Brussels sprouts conferred a low risk of lung cancer in a Cohort study of Chinese men (London et al. 2000). The effect of broccoli extract on oxidative stress in HepG2 cells using the dichlorofluorescein-diacetate assay (Kurilich et al. 2003) is reported. This study confirms the association between broccoli extracts and enhanced antioxidant activity while providing additional evidence for protection against reactive oxygen species at the cellular level (Anilakumar et al. 2006).

Anti-nutritional Activities It has been reported that GLSs have been condemned due to their goitrogenic and growth retardation activities. GLS breakdown products (oxazolidine-2-thiones) found in several oil meals may induce morphological and histological abnormalities of internal organs (Brandt et al. 2004, Halkier et al. 2006), as exemplified in increased thyroid weight in pigs and poultry, as well as depressed growth, goiters, poor egg production and liver damage. Goitrogenic activity has been associated with 5-vinyl oxozolidine-2-thione (goitrin) and thiocyanate ions. Goitrin shows its effect by interfering thyroid hormone synthesis. In contrast, thiocyanate ion, derived from glucobrassician competes with iodine for uptake by the thyroid gland. Another possible hazard from indoles is their ability to react with nitriles to form carcinogenic N-nitroso compounds. I-3- AN can react with nitrite in vitro to form compounds that have been found to be mutagenic. It is

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likely that during extraction process used in this study would have destroyed the ascorbic acid a key factor to regulate their bioactivity.

ITCs are the most toxic among the hydrolysis products, because they even affect herbivores (Agrawal and Kurashige 2003, Kos et al. 2011). Nitriles and thiocyanates have a lesser toxicity to insects (Lambrix et al. 2001, Husebye et al. 2005), whereas hardly anything is known about the biological effects of GLS-derived epithio-nitriles and oxazolidine-2-thiones on insect herbivores (Wittstock et al. 2003, Moldrup et al. 2011). It was also reported that growth retardation, liver lesions and necrosis as well as thyroid hypertrophy or hyperplasia appeared to occur when rabbits consumed diet containing 2-5 mg/g of GLSs. It is reported that I-3-C acts as scavenger of free radicals and reactive electrophiles and stabilizes biological membranes against fluidity changes. However, its anti-nutritional effects cannot be ruled out as indicated by its potential to enhance carcinogenic promotion in mouse skin, producing hepato-toxicity and neurological impairment (Lund 2003, Halkier et al. 2006). Conclusions Glucosinolates have recently attracted intense research interest because of their cancer chemo-protective attributes. Iso-thiocyanates, one of the hydrolyzed products show best anti-carcinogenic activity. Optimization of diet by including fruits and vegetables with promising quantities of phytochemicals of nutraceutical importance would be a very cost-effective method of disease prevention, since diet-induced health improvements would not carry any added costs for the health sector. References Agrawal, A.A. and Kurashige, N.S., A role for isothiocyanates in plant resistance

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Glucosinolates: The Phytochemicals of Nutraceutical Importance