Tech: Cruciferous vegetables, genetics and cancer

[Guest guest]

Hi All, The following is on cruciferous vegetables, genetics and cancer. It

seems they are inexorably intertwined. Whether broccoli is healthy for

particular ones of us depends on our genes, which in turn dictates how our

bodies metabolize the good chemicals. The different members of the family

is broader than I imagined – radish a cruciferous vegetable? Also,

mega-dosing on one is not as good as sharing the diet among different

members of the family that have different good chemicals, which act

differently to provide better health.

What I wonder, is if there is a good indicator in common blood tests to tell

if cruciferous vegetables are doing us any good.

The three papers from which excerpts are taken below are available as PDFs.

A lead-in to the rest is the definitions for the table appended and in the

files at the very end of the message and then a previous post from

http://lists.calorierestriction.org/cgi-bin/wa?A2=ind0009 & L=crsociety & P=R700

87 & X=1103891B85614E2ACD & Y=apater@..., a post in 1990 from Sherm on PMID:

11085692 [PubMed - indexed for MEDLINE].

Cheers, Al.

Latin brassica, cabbage: Any of various plants of the genus Brassica of the

mustard family, including cabbage, broccoli, and turnip.

Allium: Any of numerous, usually bulbous plants of the genus Allium in the

lily family, having long stalks bearing clusters of variously colored

flowers and including many ornamental and food plants, such as onions,

leeks, chives, garlic, and shallots.

Apiaceous: Umbelliferous: Of or pertaining to a natural order (Umbelliferae)

of plants, of which the parsley, carrot, parsnip, and fennel are well-known

examples.

London SJ, Yuan JM, Chung FL, Gao YT, Coetzee GA, Ross RK, Yu MC.

Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and

lung-cancer risk: a prospective study of men in Shanghai, China. Lancet.

2000 Aug 26;356(9231):724-9.

PMID: 11085692 [PubMed - indexed for MEDLINE]

“Chinese populations are among the most frequent consumers of cruciferous

vegetables in the world. By contrast, in the USA, the mean frequency of

intake of cruciferous vegetables is about twice a week,25 only one third the

level in a study of Chinese in Singapore.8 In our study of Shanghai men,

most had detectable isothiocyanate in the urine--the group in whom

GSTM1-null and GSTT1-null polymorphisms appear not to increase the risk of

lung cancer.”

Cancer Epidemiology Biomarkers & Prevention Vol. 9, 787-793, August 2000

Modulation of Human Glutathione S-Transferases by Botanically Defined

Vegetable Diets

……. The GSTs3 constitute a complex multigene family that, in most instances,

deactivates carcinogens, environmental pollutants, drugs, and a broad

spectrum of other xenobiotics through conjugation with glutathione (1) . The

major classes of GSTs in the liver are GST- and GST-µ (2) . A homozygous

deletion of the GSTM1 gene results in no GSTM1 activity in 50% of

Caucasians; however, because of their broad substrate specificity, other GST

isozymes (e.g., GST-) may be able to compensate for the lack of GSTM1

activity. GSTM1 also metabolizes constituents of plant foods, e.g.,

isothiocyanates (3) . GSTM1-null individuals may experience greater exposure

to dietary chemoprotective agents that are typically deactivated by GSTM1,

such that the interaction of GSTM1 genotype and dietary patterns may be more

important than either factor alone (4)

J. Nutr. 132:2991-2994,

October 2002

Brassica, Biotransformation and Cancer Risk: Genetic Polymorphisms Alter the

Preventive Effects of Cruciferous Vegetables

“The chemoprotective effect of cruciferous vegetables is due to their high

glucosinolate content and the capacity of glucosinolate metabolites, such as

isothiocyanates (ITC) and indoles, to modulate biotransformation enzyme

systems (e.g., cytochromes P450 and conjugating enzymes). Data from

molecular epidemiologic studies suggest that genetic and associated

functional variations in biotransformation enzymes, particularly glutathione

S-transferase (GST)M1 and GSTT1, which metabolize ITC, alter cancer risk in

response to cruciferous vegetable exposure. Moreover, genetic polymorphisms

in receptors and transcription factors that interact with these compounds

may further contribute to variation in response to cruciferous vegetable

intake……… genetic differences in biotransformation enzymes and the factors

that regulate them, as well as variation in glucosinolate content of

cruciferous vegetables and the methods used to prepare these foods

underscore the multiple layers of complexity that affect the study of

gene-diet interactions and cancer risk in humans.

…….. There are two main groups of biotransformation enzymes. Phase I enzymes

(cytochromes P450 and flavin-dependent monooxygenases) convert hydrophobic

compounds to reactive electrophiles by oxidation, hydroxylation and

reduction reactions to prepare them for reaction with water-soluble

moieties. Phase II enzymes (e.g., glutathione S-transferases (GST)3,

UDP-glucuronosyltransferases (UGT), sulfotransferases, N-acetyltransferases)

primarily catalyze conjugation reactions……..

Glucosinolates and human metabolism

The unique effectiveness of cruciferous vegetables to protect against

neoplastic disease is attributed to the fact that they are the richest

sources of glucosinolates in the human diet. The family Cruciferae (syn.

Brassicaceae) is comprised of familiar foods of the species Brassica

oleracea (e.g., cabbage, broccoli, cauliflower, Brussels sprouts, kohlrabi

and kale) as well as >350 other genera that include a variety of food plants

(e.g., arugula, radish, daikon, watercress, horseradish and wasabi) (5 )………

Glucosinolates (ß-thioglycoside-N-hydroxysulfates) are hydrolyzed by the

plant enzyme myrosinase when the cells in plants are damaged (e.g., cut,

ground or chewed), releasing the biologically active isothiocyanates (ITC).

If myrosinase has been inactivated (e.g., with cooking), intestinal

microbial metabolism of glucosinolates also contributes to ITC exposure,

albeit at a lower level (6 ). Even within the Brassica genus and species

different glucosinolates predominate and yield distinct ITC (5 ). For

example, glucoraphanin accounts for 35–60% of glucosinolates in broccoli

(7 ) and is converted to the ITC sulforaphane, whereas gluconasturtiin,

found in watercress, is hydrolyzed to phenethyl ITC (PEITC). Glucobrassicin

in broccoli and Brussels sprouts (8 ) is broken down to indole-3-carbinol

(I3C), which is further converted to a range of polyaromatic indolic

metabolites (e.g., diindolylmethane (DIM)) under acid conditions in the

stomach. Furthermore, glucosinolate profiles and concentrations not only

differ by Brassica species but also vary substantially across cultivars and

with different growth conditions (9 ).

The primary route of in vivo metabolism of ITC is by the mercapturic acid

pathway, a major pathway for elimination of many xenobiotics (7 ). Thiol

conjugates of ITC are formed by conjugation with glutathione, a reaction

catalyzed by GST. Subsequent stepwise cleavage of glutamine and glycine

yields L-cysteine-ITC, which are acetylated to produce N-acetyl-L-cysteine

ITC conjugates (mercapturic acids); these are excreted in urine. Thus, GST

play an important role in disposition of ITC in humans. Benzyl ITC, PEITC,

allyl ITC, and sulforaphane —common ITC in cruciferous vegetables—are all

catalyzed by the four major human GST: GSTA1-1, GST-P1-1, GSTM1-1 and

GSTM2-2; however, reaction velocities can differ by as much as 700-fold, and

there is wide variation in the extent to which ITC are disposed (10 ). Thus,

in total, human exposure to ITC is influenced by the types and amounts of

vegetables consumed, food preparation, how well food is chewed and

differences in GST isozyme profiles.

…….. in animal models and cell systems combinations of ITC confer

protection against genotoxic agents at levels that individual compounds do

not achieve alone (13 ,17 ). Because a particular Brassica species can

contain a dozen different glucosinolates (5 ), a diet high in a variety of

glucosinolate-containing vegetables may also exert synergistic effects

toward a lower-risk enzyme profile in humans.

………. relationships between GST polymorphisms and exposure to preventive

agents (i.e., ITC), with the hypothesis being that, because ITC are

metabolized by GST, polymorphisms associated with reduced GST activity will

result in longer circulating half-lives of ITC and potentially greater

chemoprotective effects of cruciferous vegetables.

…….. Polymorphisms in enzymes modulated by ITC also have the potential to

influence cancer risk. One example is CYP1A2, which activates various

procarcinogens, such as heterocyclic amines, nitrosamines and aflatoxin B1,

as well as some endogenous sex steroid hormones implicated in cancer risk

(33 ,34 ). Thus, individual differences in CYP1A2 activity may also

influence individual cancer susceptibility (35 )

………..

Experimental studies

Few human dietary interventions designed to test the effects of diet on

biotransformation enzymes have examined the effects of genetic polymorphisms

on response to diet (46 –48 ), and to date only one study has tested

gene-crucifer interactions. This controlled feeding study tested a priori if

GSTM1 genotype affects response to a diet high in cruciferous vegetables

(49 ). Men and women, recruited on the basis of their GSTM1 genotype,

completed a randomized crossover study of four controlled diet treatments

comprised of a basal diet with no vegetables or fruit and the basal diet

supplemented with a) cruciferous, allium or c) apiaceous vegetables.

Serum GST concentration, a surrogate measure of hepatic GST and an enzyme

induced by ITC, increased significantly in response to cruciferous vegetable

feeding, but only in GSTM1-null individuals. Conversely, among GSTM1+

individuals GSTµ activity in leukocytes increased in response to both

cruciferous and allium vegetable supplementation. Despite the observational

evidence for an effect of GSTM1 on CYP1A2 response to broccoli (39 ), the

increased CYP1A2 activity on the crucifer-containing diet was not affected

by GSTM1 genotype (38 ). In conclusion, relationships between cruciferous

vegetable intake and cancer risk are influenced by genetic polymorphisms in

biotransformation enzymes that metabolize ITC (e.g., GST), as well as

possibly in receptors and transcription factors that interact with these

compounds.”

Alan Pater, Ph.D.; Faculty of Medicine; Memorial University; St. 's, NF

A1B 3V6 Canada; Tel. No.: (709) 777-6488; Fax No.: (709) 777-7010; email:

apater@...

[CEBP] [AACR Cancer Prevention Conference]

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Table 3 Serum GST-[{alpha}] concentration and serum GST (NBD-C1) activity:

The ratio between response to basal and vegetable-supplemented diets

Basala Brassica/Basalb Allium/Basalb Apiaceous/Basalb

-----------------------------------------------------------------------

GST-[{alpha}], 3,605 1.13 ± 0.07c 1.02 ± 0.06 0.95 ± 0.06

pg/ml ± 378

GSTM1-null 3,041 1.26 ± 0.10 c 1.07 ± 0.09 1.00 ± 0.08

± 417

Men (n = 10) d 3,498 1.16 ± 0.14 1.05 ± 0.14 0.93 ± 0.12

± 735

Women (n = 2,644 1.38 ± 0.14c 1.09 ± 0.11 1.08 ± 0.11

15)d ± 449

GSTM1+ 4,316 0.96 ± 0.09 0.95 ± 0.09 0.90 ± 0.08

± 691

Men (n = 11)d 6,568 0.90 ± 0.11 0.95 ± 0.11 0.78 ± 0.09*

±

1,314

Women (n = 7) 2,836 1.02 ± 0.15 0.96 ± 0.14 1.04 ± 0.15

± 709

GST (NBD-C1), 75.9 ± 1.03 ± 0.02 1.02 ± 0.02 1.01 ± 0.02

units/l 2.7

GSTM1-null 70.1 ± 1.07 ± 0.03c 1.04 ± 0.03 1.05 ± 0.03

3.2

Men 71.5 ± 1.06 ± 0.05 1.08 ± 0.05 1.08 ± 0.05

5.0

Women 68.7 ± 1.08 ± 0.04c 1.00 ± 0.04 1.03 ± 0.04

3.9

GSTM1+ 82.3 ± 0.98 ± 0.04 0.99 ± 0.03 0.97 ± 0.03

4.1

Men 87.4 ± 1.00 ± 0.04 1.01 ± 0.04 0.94 ± 0.04

5.8

Women 77.5 ± 0.96 ± 0.05 0.97 ± 0.05 0.99 ± 0.05

6.2

a LS-mean ± SE, adjusted for sex, GSTM1 genotype, feeding period, and

sampling day.

b The statistical analyses for GST-[{alpha}] and GST (NBD-C1) activity were

done on the log-transformed variables. The results presented are the values

after back-transformation. The difference of the log-transformed means

after back-transformation is the ratio of the LS-means on the original

scale.

c Significant comparison between vegetable diet and basal diet (P < 0.05).

d One GSTM1-null male and one GSTM1-null female did not complete the basal

diet; one GSTM1+ male did not complete the brassica and allium diets; and

one GSTM1-null male did not complete the apiaceous diet.

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[Guest guest]

Isn't it interesting that we always get back to: Moderation and Variety.

Those two little words.......

on 10/8/2002 7:20 AM, Alan Pater at apater@... wrote:

> Also,

> mega-dosing on one is not as good as sharing the diet among different

> members of the family that have different good chemicals, which act

> differently to provide better health.