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Antioxidant vitamins make lipid lowering drugs less effective

BMJ 2001; 323 doi: (Published 08 December 2001) Cite this as: BMJ 2001;323:1323

Speaking of HMG CoA reductase inhibitors...

An unflinching determination to take the whole evidence into account
is the only method of preservation against the fluctuating extremes of
fashionable opinion.

Alfred North Whitehead (1861-1947)

Cholesterol is a 27-carbon steroid that is an essential component of
the cell membrane, the immediate precursor to steroid hormones, the
substrate for bile acids required for the absorption of fats and fat
soluble vitamin from the intestine and required for the assembly of very
low density lipoprotein (VLDL) in the liver. As such one has to believe
that this must be a compound that the body keeps under tight regulation.
Yet hypercholesterolemia, hyperlipidemia and thromboembolic disorders are
very common?

What drug companies hope is that doctors never ask themselves: What
is the normal chemical mechanism for cholesterol regulation in man? This
answer is found only in the study of nutrition.

Remember disease is considered to be a harmful deviation from the
normal structural or functional state of an organism. A diseased organism
commonly exhibits signs or symptoms indicative of its abnormal state.
Thus, the normal condition of an organism must be understood in order to
recognize the hallmarks of disease.

Most of the individuals that will read this have not been educated in
contemporary nutritional biochemistry. If they had they would understand
that Vitamin E, is an essential fat-soluble vitamin, which encompasses
eight naturally occurring compounds in two classes, not ONE!

The first class, tocopherols, have four members designated alpha,
beta, gamma and delta. The two major forms, .alpha.-tocopherol and .gamma.
-tocopherol, differ structurally only by a methyl group substitution at
the 5-position. The second class, tocotrienols, are molecules related to
the tocopherols and also consist of four members designated alpha, beta,
gamma and delta. The tocotrienol structure differs from the tocopherols by
possessing three double bonds in their side chain rather than being

In the early 80's studies of cereal grains revealed that barley was
particularly effective in lowering lipid levels in animal models. Qureshi
et al., Atherosclerosis, 51: 75-87, (1984). The ability of barley extracts
to lower lipids in vivo prompted the purification and identification of
the chemical constituents responsible for cholesterol suppressive

Alpha-Tocotrienol was recovered from barley extracts using state-of-
the-art methods and was designated as the biologically active component
based on subsequent in vitro and in vivo evaluation. Qureshi et al., J.
Biol. Chem., 261: 10544-10550, (1986). A U.S. patent was issued to The
Wisconsin Alumni Research Foundation specifically claiming the use of
alpha-tocotrienol for the lowering of lipids, U.S. Pat. No. 4,603,142, to
Qureshi et al. (1986).

The richest sources of tocotrienols are cereals (such as barley,
oats, rice, wheat and rye) and vegetable oils such as palm oil and rice
bran oil.

Tocotrienols have been shown(and are patented by Bristol-Myers Squibb
Company US 5217992) to suppress HMG CoA reductase resulting in the
inhibition of cholesterol biosynthesis and a subsequent drop in LDL
cholesterol, apolipoprotein B, thromboxane B.sub.2, platelet factor 4 and
glucose levels. (Wright, et al, A Symposium On Drugs Affecting Lipid
Metabolism, Houston, Tex. (November 1989)). In J. Biol. Chem261: 10544-
10550, (1986), Qureshi, et al. indicated that the hypocholesterolemic
effects of alpha-tocotrienol is brought about by the suppression of HMGR
as measured by hepatic HMGR activity. (Qureshi, et al, J. Biol. Chem, 261:
10544-10550, (1986)). Wright et al, supra, showed that tocotrienol-rich
fraction (TRF) fed to hypercholesterolemic swine resulted in a dramatic
decrease in serum total cholesterol and LDL-cholesterol levels. Qureshi,
et al, showed that gamma and delta-tocotrienols suppress HMGR activity.
(Qureshi, et al, Suppression of Cholesterolgenesis in Hypercholesterolemic
Humans by Tocotrienols of Barley and Palm Oils, presented at the
Antioxidant and Degenerative Diseases Conference, Berkeley, Calif.,
(January, 1990)). U.S. Pat. No. 4,603,142 to Qureshi et al., (1986)
discloses the use of alpha-tocotrienol for the lowering of lipids.

It was later discovered that Gamma-tocotrienol and delta-tocotrienol
are responsible for nearly all of the biological activity and the alpha-
tocotrienol possesses minimal biological activity towards suppression of
HMG-CoA reductase

The tocotrienols are structurally related to the tocopherols and
differ only by possessing unsaturation in the isoprenoid side chain. Like
the tocopherols, the tocotrienols have antioxidative activity, (Yamaoka,
et al, Yukagaku, 34: 120-122 (1985)). Active oxygen species are known to
play pivotal roles in the genesis of atherosclerotic plaques, thrombotic
episodes, ischemic damage, cancer, aging, dementia, and inflammatory
conditions. (Sies, H., Oxidative Stress; Academic Press, New York, (1985);
Santrucek, M., Krepelka, J., Drugs of the Future, 13: 973-996 (1988)). Of
particular interests are the potential protective effects of antioxidants
on lipoproteins, since oxidized LDL is thought to be atherogenic.
(Buckley, M., Goa, K. L., Price, A. H., Brogden, R. N., Drugs. 37: 761-800
(1989); Gwynne, J. T., Schwartz, C. J., Am. J. Cardiology, 62: 1B-77B

It is not at all surprising that statins are being considered the
next wonder drug... If one looks closely Statin drugs, they have every
property of vitamin E, especially after you take the tocotrienol faction
into consideration. Is the chemical industry stealing from nature, and not
admitting it due to conflicts of interest? Please consider that Lipitor is
the one of the best selling drugs in the world...

As far as the NEJM Vol. 345:1583-1592 is concerned. It's this simple:
There is sadly too much money in helping drug companies make money than
helping people not get diseased.

Perhaps when doctors study nutritional biochemistry and not just
clinical pharmacology the medical system would truly be healthcare, not
disease care and 'profit as usual' for the drug industry.

As long as doctors continue to be "drug brokers" there will be
continued erosion in the public's trust. Especially in those people who
know how to spot publication bias.

Competing interests: No competing interests

11 December 2001
Kenneth M Jacobie
Licensed Massage Therapist
Latham NY 12110