5[1]. Cruciferous Vegetables(1)

8/6/2019 5[1]. Cruciferous Vegetables(1)

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Cruciferous Vegetables

and Cancer Prevention


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. Introduction

As 30% of all cancers are considered to have a dietary

component.

Epidemiological studies have identified that a diet rich infruits and vegetables is associated with a decreased risk

for a number of different cancers.

Studies specifically evaluating the effect of cruciferousvegetables have shown an inverse relationship between

intake of cruciferous vegetables and cancer incidence.


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. CANCER PREVENTION BY

CRUCIFEROUS VEGETABLES

A. Epidemiological Studies There is sufficient epidemiological evidence to suggest that

consumption of cruciferous vegetables is associated with a reductionin the incidence of cancer at several sites in humans.

Review of 87 case-control studies indicated that 67% described aninverse association between crucifers and all cancers, with cabbageintake being associated with the greatest number of studies showingthis effect.

More recently a study that evaluated the effect of many individual fruitand vegetables on incidence of bladder cancer among 47,909 menrevealed that intake of crucifers, and no other vegetable typeexamined, was inversely related to risk for bladder cancer.

Epidemiological data strongly suggest that a diet rich in broccoli,cabbage, or a mixture of cruciferous vegetables is able to decrease

ones risk for cancer.


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B. LaboratoryAnimal Studies The results of studies support the epidemiological data, suggesting that

cruciferous vegetables do protect against carcinogenesis.

For example,

1. When broccoli or cabbage was incorporated into the diets of rats that

had previously received dimethylbenzanthracene(DMBA), mammary

tumor formation was inhibited.2. Brussels sprouts(20%) given in the diet before, during, and for 2 weeks

after DMBA administration also inhibited mammary tumor formation in

rats.

These, and many other laboratory studies, support the findings of theepidemiological studies.

Something distinctive about cruciferous vegetables permits them to

decrease the risk for cancer significantly.


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. CHEMICAL PROFILE OF

CRUCIFEROUS VEGETABLES

Evidence from epidemiological studies indicating that crucifers are

better able to protect against cancer than many other fruits or

vegetables leads to the logical proposal that chemoprevention by

cruciferous vegetables is associated with some unique aspect oftheir biochemistry.

Cruciferous vegetables contain a series of relatively unique

secondary metabolites of amino acids, termed glucosinolates.

While glucosinolates are not considered directly bioactive, many

glucosinolate hydrolysis products, particularly the isothiocyanates,

appear to have anticarcinogenic activity.


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The hydrolysis products are glucose, sulfate ions, and an unstable

thiono compound.

The unstable thiono intermediate can rearrange to form an

isothiocyanate, a nitrile, or a thiocyanate, depending upon such

conditions as pH, temperature, presence of iron, and extent of

hydration.


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The major glucosinolates and their bioactive hydrolysis products

from the common Brassica vegetables are shown in Table.

A wealth of information is available on the chemistry and bioactivity

of glucosinolate hydrolysis products.


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. MECHANISMS OF

CHEMOPREVENTION

In seminal studies planned to determine the mechanism of cancer

prevention by isothiocyanates, Wattenberg treated rats with a single

dose of benzyl isothiocyanate, either 24, 4, or 2h before, or 4h after,

giving the carcinogen DMBA.

When he administered benzyl isothiocyanate in the diet starting 1

week after DMBA treatment, fewer breast tumors developed.

It has become increasingly clear that the anticarcinogenic effects of

isothiocyanates are unlikely to be due to a single mechanism, or even

limited to a single stage of ccarcinogenesis.


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A. Induction Of Detoxification The major mechanism of chemoprevention by cruciferous vegetables is

thought to be through upregulation of detoxification enzymes, resulting

in decreased initiation of chemical-induced carcinogenesis.

500g of broccoli/day for 12days

-> increased cytochrome P450(CYP)1A2-dependent caffeine metabolism,

it did not alter CYP2E1-dependent chlorzoxazone metabolism.: This data indicate that dietary crucifers can increase detoxification enzymes

in humans.

Glucosinolate hydrolysis products upregulate through at least two

response elements in the genes of detoxification enzymes: (1) bifunctional inducers interact with the xenobiotic response element

(XRE), also termed the aryl hydrocarbon response element(AhRE),

(2) monofunctional inducers interact with the antioxidant response

element(ARE).


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B. Inhibition ofActivation A large number of precarcinogens are bioactibated to the ultimate

carcinogen by CYP-dependent oxidation. It has been proposed that glucosinolate breakdown products may

protect against initiation of cancer not only by induction of phasedetoxification enzymes, but also by inhibiting CYP-dependent activation

of precarciongens.

Very recently benzyl isothiocyanate was shown to cause the

destruction of CYP2E1 during metabolism.

In a temporal study using rats, PEITC was found to cause a significant

loss of CYP1A1/2 and CYP3A activity, in addition to the sever loss ofCYP2E1 activity.

In contrast to the in vitro study that had reported acute inhibition of

CYP2B enzyme activity, here PEITC was found to induce CYP2B

enzymes.


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C. Inhibition of Cell Proliferation and Apoptosis

In a separate study using the human undifferentiated colon cancer cell

line HT28, the parent glucosinolate, glucobrassicin, was shown to have

no effect, while the hydrolysis products diindolyl methane and

sulforaphane decreased cell viability by approximately 50%.

Studies have also implicated cell cycle arrest.A study in HeLa cells

reported that allyl isothiocyanate, benzyl isothiocyanate, and PEITC all

caused cell cycle arrest at G2/M.

Isothiocyanates have been found to cause apoptosis in vitro.

c-Jun N-terminal kinase(JNK), which lies upstream of caspase 3 in the

apoptotic cascade, was also actibated by isothiocyanates.


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. DEVELOPMENT OF CANCER PREVENTATIVE

AGENTS FROM CRUCIFEROUS VEGETABLES

The cancer preventative activity of isothiocyanates derived from

hydrolysis of glucosinolates.

The majority of the work has focused on just a few, including indole-3-carbinol, PEITC, sulforaphane, and benzyl isothiocyanate.

Scattered studies have shown protection from other indolyl

compounds, such as brassinin, which gas been shown to protect

against mammary carcinoma and skin tumors in mice given DMBA,and allyl isothiocyanate, effective in combating colon carcinogenesis.


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A. Phenylethyl Isothiocyanate(PEITC) Watercress is a particularly good source of gluconasturtiin, the

parent glucosinolate to PEITC.

In an evaluation of the effect of PEITC on NNK bioactivation in rats,

it was found that PEITC(1 mmol/kg rat) had an inhibitory effect on

CYC2E1, effectively blocking the bioactivation of NNK.Also,

PEITC induced a number of phase enzymes which could thenclear any bioactivated products that were formed.

One study reports that, when PEITC and benzyl isothiocyanate

were given postinitiation to rats that had received the urinary

bladder carcinogen diethylnitrosamine, there was a significantincrease in papillary hyperplasia and carcinoma compared with

rats receiving the carcinogen alone.


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B. Indole-3-Carbinol

A breast cancer prevention trial is being conducted at Strang CancerCenter, based on mechanistic studies showing that in three breast cancercell lines, indole-3-carbinol caused a>50% inhibition in growth, with anincrease in the quiescent cell fraction, and a doubling of the apoptotic rate.

Indole-3-carbinol condensation products have the ability to bind to theSRE and cause induction of CYP1A1/2, which is involved in thebioactivation of many precarcinogens.

When indole-3-carbinol was administered to mice prior to the pulmonarycarcinogen NNK, pulmonary NNK-DNA adduct formation was decreased,but hepatic NNK-DNA adduct formation was increased.

Indole-3-carbinol and at least some of these condensation products havean interactive effect with estrogen, affecting estrogen metabolism and

estrogen binding to the estrogen response element.

A number of studies in rodents and humans show that indole-3-carbinolcauses an increase in 2-hydroxylation of estrogen, increasing the ratio of2:16 hydroxylated products.


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C. Sulforaphane and Sulforaphane Analogues

Sulforaphane decreases mammary tumor incidence when

administered to rats before and during administration of DMBA, and

inhibits neoplastic nodule formation in mouse mammary gland

cultures.

When sulforaphane and compound 30were administered to rats

given DMBA, they were both effective as anticarcinogens.


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. BIOACTIVE COMPONENTS

OTHER THAN ISOTHIOCYANATES

A. Crambene

In evaluation of glucosinolate hydrolysis products asanticarcinogens, almost all the research has focused onisothiocyanates.

Studies have revealed that crambene is a monofunctionalinducer, causing upregulation of quinone reductase andglutathione transferase while having no effect onCYP1A1/2 levels.

When rats were given both crambene and indole-3-

carbinol together, total upregulation of quinone reductasewas significantly greater than expected when addingtogether their individual effects.

B. S-Methyl Cysteine Sulfoxide(SMCSO)

Crucifers contain high levels ofSMCSO.


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C. Dithiolethione The natural dithiolethione present in cruciferous vegetables.

Both dithiolethione and oltipraz(antischistosomal drug) have been shown

to upregulate phase enzymes via theARE, making them classic

monofunctionall inducers.

Healthy adults three groups

1group : given either a placebo

2group : given 500mg oltipraz once weekly

3group : given 125mg oltipraz daily

after 1 monthurinary analysis revealed that the intermittent high dose inhibited phase

Bioactivation of aflatoxin, while daily low-dose oltipraz increased phase

detoxification of bioactivated aflatoxin.


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. SAFETY OF CRUCIFEROUS

VEGETABLES

Genotoxicity of vegetable extracts

Brussels sprouts > cauliflower > cabbage, kohlrabi, broccoli > Turnip(This ranking was not strictly related to total isothiocyanate content, but the authors suggested that this

might only be because individual isothiocyanates differ in their genotoxic potency.)

Isothiocyanates were both promoters and complete carcinogens,

initiating cancer and promoting mitosis of mutant cells.

Cruciferous vegetables gave been a part of the diet for many centuries.

Any compound exhibiting bioactivity can be expected to exert adverse,

or toxic, effects at sufficiently high doses.

The meal from industrial oilseeds is high in glucosinolates, often

containing 3 to 7% glucosinolates by weight. In contrast, cruciferous

vegetables contain 0.02% to 0.4% glucosinolate by weight, althoughlevels in cruciferous vegetable seeds are typically tenfold higher than in

the plant.

Therefore, intake of cruciferous vegetable seeds as a significant

percentage of the diet could produce adverse effects.


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. IMPACTING THE AMERICAN

DIET When glucosinolates isolated from Brussels sprouts were fed to rats, they

had no measurable effect on clearance of the drug antipyrine unless theywere first hydrolyzed by adding myrosinase. When the hydrolyzed

products were fed to rats, antipyrine clearance was increased by 66%.

Information of this type has been used to suggest that glucosinolate

breakdown products are the active molecules in upregulation ofdetoxification enzymes. This is important as one considers whether it is

better to cook cruciferous vegetables or eat them raw to obtain their

health benefits.

Most animal studies have been carried out using freeze-dried raw

vegetables. While there are relatively few human studies, most have

employed cooked vegetables. Feeding cooked cabbage(200g/day)and

Brussels sprouts (300g/day)to humans caused an increase in

detoxification enzymes, and feeding cooked brussels sprouts(300g/day)

decreased oxidative DNA damage.


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New broccoli products, including broccoflower and broccolini are on

the market, but glucosinolate levels in these varieties are not yet

reported.

Tablets containing broccoli and other cruciferous vegetables are

becoming available in health food stores.

Crucifers offer a valuable health benefit to the diet that may not beobtained through other functional foods.

Only time remains before there are cruciferous cultivars

commercially available that are nutritious, palatable, and sufficiently

potent when integrated into the diet on a regular basis, to offer

protection from the risks of cancer.


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. SUMMARY

A diet rich in cruciferous vegetables, such as broccoli and cabbage, is

associated with a decreased risk for a number of cancers.

Crucifers contain a family of secondary plant metabolites known as

glucosinolates.

Isothiocyanates have also been shown to increase or upregulate

several detoxification enzymes.

Crucifers may act through inhibition of cytochrome P450-dependent

bioactivation of carcinogens resulting in decreased initiation of cancer

and, through cell cycle arrest and apoptosis, resulting in decreased

progression of tumor growth.

Documents

5[1]. Cruciferous Vegetables(1)