To E or Not to E?

[Guest guest]

Hi All,

To " E " or Not to " E? Is that the question?

The below paper seems to suggest that

we should " E " ?

The PDF is available for the below.

It is not yet in Medline, but the author writes

many " Abstract not available " NEWS AND ANALYSIS

papers.

Cheers, Al Pater.

NEWS AND ANALYSIS

Medical News & Perspectives

To " E " or Not to " E, " Vitamin E's Role in Health and Disease Is

the Question

M.J. Friedrich

JAMA. 2004;292:671-673.

BOSTON—From the pharmacy shelf to

the kitchen shelf, vitamin E has be-come

a common presence—not sur-prising

for a substance touted as some-thing

that can help prevent and treat

maladies ranging from cardiovascular

disease to cancer. A good deal of labo-ratory

data and results from epidemio-logical

and retrospective studies sup-port

the notion that vitamin E can help

ward off myocardial infarctions and

keep cancer at bay.

Findings from a variety of random-ized

controlled trials, however, have

failed to show consistent health ben-efits

and many questions remain un-answered

about this micronutrient. But

don't chuck the bottle of vitamin E into

the trash bin yet. A group of leading vi-tamin

E researchers gathered here in

May for a conference on Vitamin E and

Health sponsored by the New York

Academy of Sciences reviewed evi-dence

of the role this vitamin plays in

human health and disease and dis-cussed

new information that recently

has begun to emerge.

Vitamin E is known primarily as an

antioxidant that helps rid the body of

damaging free radicals, which can

wreak havoc on cells and DNA by in-creasing

the oxidative stress associ-ated

with many diseases. But the

vitamin also appears to perform nonan-tioxidant

functions that may benefit

health by exerting anti-inflammatory

actions and anticoagulant effects and by

regulating genes and immune func-tion.

A more nuanced understanding of

vitamin E's various functions is needed,

conference participants said, to deter-mine

the most useful approaches in us-

ing this substance to maintain health

and combat disease.

HEART HEALTHY?

Perhaps one of the most perplexing

questions surrounding vitamin E is its

role in cardiovascular disease. Oxida-tive

modification of low-density lipo-protein

cholesterol is considered a key

step in the initiation and progression

of atherosclerosis. Antioxidants such as

vitamin E have been studied to deter-mine

their ability to modulate such oxi-dative

damage and thereby decrease the

risk of heart disease.

But as J. Gaziano, MD, MPH,

of the Brigham and Women's Hospi-tal,

Boston, pointed out, the vitamin E

story is " a little unusual in epidemiol-ogy. "

While the basic science litera-ture

suggests plausible mechanisms by

which vitamin E can reduce athero-sclerotic

events and observational stud-ies

support this association, results from

clinical trials have been conflicting in

that some have shown a clinical ben-efit

(Lancet. 1996;347:781-786) while

others have not (Lancet. 1999;354:447-

455; N Engl J Med. 2000;342:154-

160). A recent meta-analysis of 7 ran-domized

trials of antioxidant vitamins

for the prevention of cardiovascular dis-ease

concluded that the data at this time

do not support the routine use of vita-min

E supplements for this purpose

(Lancet. 2003;361:2017-2023).

Researchers at the conference pointed

out that the clinical trials differed from

each other in a number of important as-pects,

such as selection of subjects, stage

of disease, end points, dosage, and

source of the vitamin—differences that

have contributed to the inconsistent

findings and that make the trials diffi-cult

to compare. Future trials that ad-dress

these limitations should help pro-vide

a clearer picture of vitamin E's role

in cardiovascular disease.

Another important issue, said Fran-cesco

Violi, MD, of the Universita La

Sapienza, Rome, is that not all pa-tients

at risk for cardiovascular dis-ease

have high levels of oxidative stress,

but no trial took this into account.

Therefore, said Violi, a more targeted

approach would be to include only pa-tients

with enhanced levels of oxida-tive

stress and low vitamin E plasma lev-els

in order to study those most likely

to benefit from antioxidant treatment.

BEYOND alpha-TOCOPHEROL

Most clinical trials designed to exam-ine

the ability of vitamin E to prevent

disease have included the form of vi-tamin

E called alpha-tocopherol, the most

abundant form of the vitamin and the

primary compound used in dietary

supplements. But recent molecular and

epidemiological studies have prompted

researchers to look beyond alpha-tocoph-erol

to the other forms of vitamin E such

as gamma-tocopherol.

Naturally occurring vitamin E is ac-tually

a complex of 8 chemical com-pounds:

4 tocopherols (alpha, beta, gamma, and delta)

and 4 tocotrienols (alpha, beta, gamma, and delta).

While gamma-tocopherol (found in corn, soy-bean,

and sesame oils and walnuts, pea-nuts

and pecans) is the most common

form of vitamin E in the US diet, gamma-to-copherol

levels are generally 10 times

lower than levels of alpha-tocopherol in

plasma. For this and other reasons, sci-entists

have placed a greater focus on

alpha-tocopherol

Until recently, that is. Cancer re-searchers

in particular have begun to pay

closer attention to gamma-tocopherol. Inter-est

is shifting to the gamma compound in part

because results from a number of large,

prospective studies examining the pre-ventive

effects of alpha-tocopherol on can-cer

have been inconsistent. However, it

should be noted that one study did show

an association of alpha-tocopherol with a

reduced incidence of prostate cancer

(J Natl Cancer Inst. 1998;90:440-446).

These results will be explored further in

the Selenium and Vitamin E Cancer Pre-vention

Trial (SELECT), a large, pro-spective

trial of selenium and alpha-tocoph-erol

in more than 30000 men (

http://www.nci.nih.gov/select ).

But could alpha-tocopherol be even more

effective when paired with the gamma com-pound?

A recent study showed that in-creased

levels of gamma-tocopherol were as-sociated

with a significantly reduced

risk of prostate cancer ( J Natl Cancer

Inst. 2000;92:2018-2023). The research-ers

also found that protective effects of

high concentrations of selenium and

alpha-tocopherol were only observed when

gamma-tocopherol concentrations were high.

This study and others are raising ques-tions

about gamma-tocopherol's effects on

other types of cancer.

COLON CANCER CONNECTION

Stone, PhD, of East Tennes-see

State University, City, and

colleagues are investigating whether

gamma-tocopherol can inhibit the growth of

colon cancer. He hypothesizes that in-tracellular

levels of vitamin E are more

important than plasma levels in pro-tecting

cells against the molecular

mechanisms that can lead to cancer.

Part of the rationale for his work

with gamma-tocopherol is that this com-pound

is taken up by colon cancer

cells much more effectively than

alpha-tocopherol. And when alpha- and

gamma-tocopherol are taken up together

into cells, the presence of gamma-tocopherol

increases the level of alpha-tocopherol.

These findings, said Stone, raise the

issue " of whether we can really think

of alpha- and gamma-tocopherol as separate, if

one influences the absorption of the

other. "

In addition, said Stone, gamma-tocoph-erol

has some unique properties that

alpha-tocopherol does not have, includ-ing

the ability to reduce nitrogen diox-ide

to antioxidant nitric oxide, along

with the ability to suppress the expres-sion

of the ras-p21 gene, which en-codes

a protein known to promote

oncogenesis.

In a study done in rats, Stone and col-leagues

found that gamma-tocopherol plays

a significant role in providing antioxi-dant

protection to the epithelial cells of

the colon and to fecal material (possi-bly

decreasing the production of mu-tagens

from the oxidation of fecal

lipids). In addition, they found that

expression of the cancer-promoting

gene ras-p21 was decreased by gamma-tocopherol,

but not alpha-tocopherol (Can-cer

Detect Prev. 2002;26:78-84).

Stone's group also examined the in-fluence

of gamma-tocopherol on the expres-sion

of another gene, peroxisome pro-liferator

activated receptor-gamma (PPAR-gamma),

a promising target for colon cancer pre-vention.

Activation of PPAR-gamma with

drugs such as troglitazone can reduce

tumor growth by inhibiting cellular pro-liferation

and inducing programmed

cell death, or apoptosis, said Stone.

Because vitamin E possesses struc-tural

similarities to troglitazone, Stone's

group wanted to determine whether

vitamin E could also regulate PPAR-gamma.

In colon cancer cell studies, they found

that while both gamma- and alpha-tocopherol

could upregulate PPAR-gamma protein ex-pression

(produce more of the protein),

gamma-tocopherol was much better at this

task than its alpha cousin (BMC Cancer.

2003;3:25). The effect, suggested Stone,

might be due to the ability of gamma-tocoph-erol

to accumulate at higher concen-trations

in colon cells.

TOCOTRIENOLS AND BREAST CANCER

Yet another form of vitamin E may be

a better preventive agent than alpha-to-copherol

in stemming breast cancer

growth. Tocotrienols, the major vita-min

E components in palm oil, seem

to be the more promising compounds

in breast tumors, said Kalanithi

Nesaretnam, PhD, of the Malaysian

Palm Oil Board, Kuala Lumpur. She

noted that the body naturally concen-trates

these compounds in adipose tis-sue,

the main type of tissue that con-stitutes

the breast.

Nesaretnam and colleagues have

demonstrated in cell culture and ani-mal

studies the ability of tocotrienols—

primarily the gamma and delta versions—to in-hibit

breast cancer cell growth in both

estrogen-dependent and estrogen-independent

cells (Lipids. 1998;33:461-

469). Apoptosis is one of the mecha-nisms

by which tocotrienols may inhibit

tumor growth (Nutr Cancer. 1999;33:

26-32).

Nesaretnam pointed out that that

alpha-tocopherol has been shown in some

studies to inhibit breast cancer cell

growth, but cell culture studies show in-hibiting

cancer cell growth requires

much higher levels of alpha-tocopherol than

of tocotrienols. (She noted that the form

of alpha-tocopherol that brought about in-hibition

in breast cancer cell lines is alpha-tocopherol

succinate—not alpha-tocoph-erol

acetate, which is what is found in

most commercial preparations of vita-min

E.) In addition, although alpha-tocoph-erol

succinate has been shown to achieve

inhibition of tumor growth in vivo, this

is seen only when the compound is in-jected

into the tumor. In contrast, her

group has found that tocotrienols taken

orally suppress breast tumor growth in

mice (Lipids. 2002;37:557-560).

Tocotrienols have been shown to po-tentiate

the antiproliferative effects of

tamoxifen in both estrogen-depen-dent

and estrogen-independent breast

cancer cells in culture. Using this as a

rationale, Nesaretnam and colleagues

have begun a clinical trial in Kuala

Lumpur to look at the effects of tocot-rienols

in combination with tamoxi-fen

in 240 women with stage 1 or 2 es-trogen-

dependent breast cancer. The

end points will be recurrence of dis-ease

and metastasis.

Using microarray technology to study

the specific genes regulated in breast

cancer cells by tocotrienols, Nesaret-nam's

group has identified a few genes

involved in inhibiting cell growth and

differentiation. These results suggest

that tocotrienols affect cell homeosta-sis

independently of their antioxidant

activity, she said.

NEW HORIZONS

While research continues into the

antioxidant actions of vitamin E, the

vitamin's nonantioxidant functions

are beginning to steal the spotlight,

said, Lester Packer, PhD, of the Uni-versity

of Southern California, Los

Angeles, one of the conference's orga-nizers.

In addition, vitamin E shows

promise in illnesses ranging from Alz-heimer

disease, preeclampsia, and

upper respiratory tract infections in

the elderly.

" Whole new approaches to under-standing

vitamin E in biological sys-tems

and in health and aging have

arisen in recent years, " he said. The

hope, said Packer and other experts, is

that such approaches will provide in-sights

that will open up new avenues

of research and lead to tangible ben-efits

for patients.