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From: (Steven B. Harris )
Subject: Re: Vitamin E
Date: 07 Oct 1995

In <> (Jim
Atwell) writes:

>Hello Steven,
>On the 30 Sep 95, at 16:22, Steven B. Harris  wrote to All:
> SBH> From: (Steven B. Harris )
> SBH> You can go up to 800 U of E (divide in two doses with
> SBH> meals) without toxicity
>GASP!  I've been taking 1000 U a day for about a year now!   :-)

   I didn't mean that toxicity began at 800-- in fact I know of no
believeable studies which have found ANY toxicity, even at huge doses
of 3200 IU and more.  You can take so much vitamin E that your skin
starts to get oily with exuded vitamin E! (There were some studies in
the 1970's which reported a flue-like syndrome with vit E, even at 400
IU, but this went away and has never been seen again.  It just have
been either hysteria or a bad vit E batch).  But 800 is the biggest
dose for which we have a very large population who have been followed
for rare effects of toxicity.  Above that, therefore, you're
theoretically less safe.

From: B. Harris)
Subject: Re: Antioxidants and injury
Date: 12 Apr 1997

In <01bc475b$4796ea40$78590acb@user> "iceman" <>

>As yet have had no response to the article. Any information would be great.
>Any feedback or ideas would also be appreciated.
>iceman <> wrote in article
>> We are starting research examining the effects of antioxidants on recovery
>> from acute muscle strain injuries. Is anybody aware of any research in the
>> area that has already been done? We haven't found any as yet (including
>> medline search). Any help or information would be greatly appreciated!

   I've seen several studies on vitamin E and post-exercise muscle
damage as measured by CPK elevations.  It helps.   I don't know why you
haven't found them with a medline search, but it might help if you use
CPK as a search term (textword).  Also "exercise."

From: B. Harris)
Subject: Re: Natural versus synthetic vitamin supplements
Date: Tue, 16 Dec 1997

In <> (C.J. Fuller) writes:

>In article <675feg$hg1$>, Bryan Shelton
><> wrote:
>[snipped for brevity]
>>Lately in this group there's been a sort of revisionism going on about
>>natural vs. synthetic vitamin E. I've always used cheap synthetic brands
>>but now I'm starting to wonder about what seems to be a growing feeling
>>among the experts that maybe there's a kind of undesirable competition
>>between the "d" and "l" forms that constitute the synthetic product. Are
>>you still of the opinion that there's no reason to spend one extra cent
>>on natural vitamin E, because an IU is an IU is an IU...?
>Yes.  Unless and until the vitamin peddlers package their products in mg,
>stay with synthetic.  An IU is an IU is an IU.

   True, if you're an E deficient rat looking to keep your fetal pups
from being resorbed.  And don't have a lot of money to spend doing it.

    For the rest of us, there is indirect evidence from studies in
several species that the d isomer is handled and retained enough
differently from the l isomer to be worth the money, and more.  And
with the nasty example of D-carnitine before us, I'm not sure that for
the little bit of extra money I really want any unnatural l.   I can't
prove that hunch, of course.  Meanwhile, you're welcome to save that
nickel and take your chances.

                                        Steve Harris, M.D.

From: B. Harris)
Subject: Re: Natural versus synthetic vitamin supplements
Date: Wed, 17 Dec 1997

In <677fj1$44p$> (Keith Howie) writes:

>On 16 Dec 1997 23:22:17 GMT, B. Harris)
>>    For the rest of us, there is indirect evidence from studies in
>>several species that the d isomer is handled and retained enough
>>differently from the l isomer to be worth the money, and more. And with
>>the nasty example of D-carnitine before us, I'm not sure that for the
>>little bit of extra money I really want any unnatural l. I can't prove
>>that hunch, of course. Meanwhile, you're welcome to save that nickel and
>>take your chances.
>I do a fairly good job of keeping up with what's going on in the
>nutrition field, but I don't know what you mean by "the nasty example
>of D-carnitine". Please elaborate.

   It causes symptoms of carnitine deficiency.  Making therapy with DL
carnitine somewhat less than successful <g>.  Which is why you no
longer see this sold.

From: B. Harris)
Subject: Re: VitE why not dl-Alpha tocopheryl?
Date: 3 Apr 1998 09:02:25 GMT

In <> Tom Matthews <> writes:

>In addition, the alpha tocopheryl succinate (synthetic, I believe)
>appears to have additional anticancer effects that the other vitamin E
>forms do not have. My dosage recommendation is 400 IU mixed natural
>tocoperols plus 800 IU tocpheryl succinate.

   Be aware that the 400 IU "natural mixed tocopherols" is 400 IU of
d-alpha only, with usually unknown amounts of the "natural mixed
tocopherols".  In products which have ONLY the natural mixed
tocopherols (ie, the LEF product), you won't find any IU rating at all,
because these products are mostly gamma tocopherol (which is mostly
what's in natural oils), and FDA prohibits IU label ratings for
anything but alpha.  Even though gamma surely has vitamin E activity.

   Now how's this for a horse laugh:  the FDA will let you count the
vitamin activity of the unnatural l-alpha tocopherol on the label, but
the natural d-gamma and d-delta cannot be counted.  Go figure.

                                       Steve Harris, M.D.

From: Steven B. Harris <>
Subject: Natural vs. Sythetic Vit E
Date: Fri, 01 May 1998 22:01:10 GMT

     A recent study in Am. J. Clin. Nutr. (67:669-84), 1998, confirms in
humans what had previously been suspected in pigs.  Natural vitamin E is
twice as potent as the synthetic, due to being retained twice as well in
the body.  The officially defined ratio of potency (derived from a rat
assay which isn't relevent to rats, let alone humans) put the potency
ratio of the two products at 1.36.  What this means in practive is that
when you buy a bottle of synthetic vitamin E (the label says "dl-alpha"
rather than "d-alpha" tocopherol), you're getting only about 68% of the
"I.U." potency shown on the label.  Not such a big deal, but interesting.

    The new study labeled synthetic dl-tocopherol (8 isomers) and natural
d-tocopherol and administered them to humans in high and low doses, in
the range of supplements.  It found that the ratio in tissues of the two
compounds was generally about 2:1.  The difference is probably caused by
the dl isomerism at only one point (one of three chiral centers in the
molecule, which is the only one which the body recognizes.  It probably
completely ignores the "wrong" isomer in this case, giving half the
tissues levels.

Steven B. Harris. M.D.

From: B. Harris)
Subject: Re: Vitamin E - More the better?
Date: Mon, 13 Oct 1997

In <61s1i2$n20$> Bryan Shelton
<> writes:

>Marty, to show the great trust that I (and many others in this group, I'm
>sure) have in your knowledge and also in your flexibility as NEW data
>becomes available, I went out yesterday to my favorite health-food store
>to check out the mixed-tocopherols for the first time ever.  I found many
>different brands, of course, but I was APPALLED at one thing I found:
>every single brand contained their mixed-tocopherols in an UN-ESTERIFIED
>form!  What the hell is going on?!  I'm certainly not gonna take any of
>MY vitamin E as straight un-esterified tocopherols!

Comment:  Why not?  The succinate might have extra interesting
properties as a lipid antioxidant, a bit like ascorbyl palmitate (the
esterified version of vitamin C), but that doesn't mean that the
unesterified E's are bad for you, or don't work.  On the contrary, if
they are in there, they're helping to keep the capsule contents from
being oxidized (something the esters can't do while they are esters).

                                  Steve Harris, M.D.

From: B. Harris)
Subject: Re: Vitamin E - More the better?
Date: Wed, 15 Oct 1997

In <> writes:

>> What Steve meant, Bryan, was the vitamin activity of one kind of E
>> compared with another kind of E.
>No, I don't think that's what Steve meant.  When he said "That tells
>me that the vitamin activity ISN'T JUST GENERIC ANTIOXIDANT POWER" it
>seems obvious to me that he was addressing the age-old conventional
>wisdom that the ONLY function of vitamin E is AS AN ANTIOXIDANT.  But
>for heaven's sake, let's get it straight from the horse's mouth: Steve,
>please clarify *precisely* what you meant!
>> What you are missing, and Steve statement didn't help you to see, is
>> that chemically different anti-oxidants has effects in the body which
>> may be quite unrelated to their *raw oxidizing power*. That is why I
>> wrote in another post that is it rather meaningless to make claims that
>> compound "X" had 10 times the anti-oxidant power of compound "Y". Once
>> into the body, the various antioxidants are transported in various ways
>> to various targets. As I recall, vitamin E is transported in the plasma
>> lipids, particularly the cholesterols as they are made in the liver. The
>> above distinction between the sterioisomers of vitamin E shows to me
>> that this uptake and transport mechanism may be quite geometry dependent
>> which would not be unusual. In fact, this transport system may *only* be
>> efficient for d-alpha-tocopherol and this may be the reason why the
>> beta, gamma, and kinds do not show the same *vitamin E* activity, even
>> though as has now been shown they are very necessary.
>Oh, I'm profoundly aware of all this, Tom!  But you still ignore the
>point that BHT, for example, is much more potent than vitamin E as an
>antioxidant and is also lipid-soluble;	it's certainly going to work its
>way into similar places as vitamin E including lipoproteins, if I recall
>correctly. Yet no one has ever accused BHT of having ANY vitamin E
>activity.  Even though they obviously overlap in some activities like
>protecting red blood cells from oxidative damage, when it comes to more
>subtle things (like the rat resorption gestation test) BHT does NOT show
>any vitamin activity. (Someone please correct me if I am wrong here.)
>This is what I believe Steve was also referring to. Steve, please

    The partial vitamin activity of some antioxidants (ethoxyquin)
suggests that some of vitamin E's vitamin activity is simply as an
antioxidant.  The fact that no antioxidant can completely substitute
for E suggests that it does other things as well.  Also the fact that
the antioxident activity of various E vitomers doesn't correlate with
their antioxidant power is a clue that this is not all that is going
on.  Of course, none of this is proof.  It might be instead that all we
are seeing here is differences in the body's transport system for the
different antioxidents and vitomers, and E really DOES do nothing at
the endpoint but act like an antioxidant.  We might protest that it odd
that the body works so hard to transport something somewhere to be an
antioxidant, if it isn't the most powerful available antioxidant.
However, perhaps part of the answer is in affinities for different
oxidizing species, as in the recent well-publicized findings that gamma
tocopherol likes to particulary quench peroxynitrite (superoxide +
nitric oxide).   Not all oxidants are alike, and vitamin activity by
one assay may depend on the job that needs doing.  Perhaps d alpha
tocopherol has the greatest vitamin E activity in the rat fetal
resorption test because it is more specific for the oxidizing species
that chew on rat fetuses, whatever those might be.  Perhaps if we had a
vitamin E assay more sensitive to something that was screwed up by
peroxynitrite, gamma tocopherol might come out with greater "vitamin E

                                          Steve Harris, M.D.

From: B. Harris)
Subject: Re: Mixed Tocopherols in Vit E caps?
Date: 18 Feb 1998 23:22:35 GMT

>:This information is from Puritan's Pride:  Confusion often results when
>:referring to Vit. E since it is available in many different forms. If
>:alpha tocopheryl acetate or alpha tocopherol is preceded by dl or just
>:just stated as alpha tocopheryl acetate or alpha tocopherol, then it is
>:     Confusion also results regarding the spelling of tocopherol. Ol
>:means that the Vitamin E contains all four of the tocopherols (alpha,
>:beta, gamma and delta).  If it is spelled with a yl, the Vitamin E only
>:contains alpha tocopheryl, the other oils have been extracted.
>:   Hope this helps, :)Judy

    It doesn't help, because it's all wrong.  The -ol ending signifies
the free alcohol.  You never see it with acetate or succinate, which
are esters of the alcohol, and will have the -yl.  Thus, tocopheryl
acetate or tocopheryl succinate.  The -ol won't have anything -ate.

     The alpha signifies the alpha vitamer, which is the molecule with
more methyl groups than the delta, beta, or gamma isomers.  The "dl"
alpha product molecules are made by total synthesis starting with no
natural vitamin E base, and are actually a mixture of not two, but
eight isomers (they have 3 chiral centers, each of which is a 50/50 dl

    When you see d-alpha instead of dl-alpha, you know that you're
looking at single isomer, *but* you must know that you still have a
semi-synthetic product, inasmuch as 80% of the d-alpha tocopherol (or
tocopheryl esters) on the market are made by methylating delta and
gamma tocopherols extracted from oils.

    So called "mixed tocopherol" capsules contain mostly d-alpha, but
the company also adds a little bit of the standard gamma,delta,alpha
mixture which naturally occurs in soybean oil extracts (this is mostly
gamma, then delta, since these are the ratios that occur naturally in
oils).  This natural mix will always be less than 20% of the total
tocopherols, since the FDA prohibits companies from expressing the I.U.
vitamin content of vitamin E preparations calculating with anything but
the alpha tocopherol(yl) content.  So the other isomers are "wasted" in
that regard, and the vitamin company doesn't want them taking up space
if they don't contribute to the bottle label international unit
activity "I.U." number (of course, we know that gamma and delta
tocopherols have vitamin E activity, but whoever said that the FDA's
edicts had to make sense?).  Thus, their low content in commercial

    You never know how much gamma or delta tocopherol is in your
"mixed" preparation, because no company will tell you on the label.
You just know that it's low.  There is a product made by the Life
Extension Foundation that is nothing BUT mixed tocopherols (mostly
gamma), but they don't (can't by law) give you any equivalent I.U.
activity rating.

                                   Steve Harris, M.D.

From: B. Harris)
Subject: Re: Your Expensive Urine--- Ahem
Date: 26 Feb 1998 19:42:42 GMT

In <> marcie rekenn <>

> 4 gms of Tylenol would be
>8 extra strength tablets daily - a very high dose and not one people
>tend to use on a constant basis.  10 gm would be 20 such tablets -  an
>overdose by anyone's measurement. The heart protective dose of aspirin
>is i/2 of a 325 mg tablet/day, which can be in the enteric coated form
>which eliminated the GI problem. This dose of aspirin has never been
>shown to be toxic to the kidney.

   True enough about aspirin and the kidney at those doses.  Enteric
coating and also buffering of aspirin, alas, doesn't entirely eliminate
GI problems.  These come from inhibition of prostaglandins in the
stomach, and the best you can do is get the dose of aspirin as low as
possible (40 mg a day or so-- 1/2 of a baby aspirin, which will still
give full antiplatelet effect).  In the PHS study, there were still
significantly more severe GI bleeds in the group getting 365 mg of
aspirin every other day-- possibly all due to antiplatelet effects, but
maybe not.

>Vitamin E on the other hand is toxic to anyone on digitalis, or
>who has rheumatic heart disease.

    The digitalis interaction is not well documented, and I frankly
don't believe it.  Vitamin E increases afterload temporarily, which can
cause problems in people with severe mitral regurgitation (as in some
cases of rheumatic fever valve damage), and most people with congestive
heart failure.  Since these effects are temporary, doctors who are
vitamin E enthusiasts have been able to get away giving vitamin E even
to these people, by working up the dose gradually.  But it's definitely
not something to try on your own, if you're being treated for heart

> It can also do temporary damage to the liver

   Vitamin E?  Baloney.  There were a few reports of elevated liver
enzymes in the 1970's, but they haven't been seen again.  Perhaps
contamination with something else in a bad batch of E?

> and may cause severe GI symptoms in some people.

    Vitamin E?  You must have gotten a bad batch.  The largest human
trials find none of this.  Again, you have to go back to the 1970's
"flu-like syndrome" scare to see any of this.  And that was (I think)
either bad product or hysteria, because it hasn't been seen since.

> BTW combining aspirin and fish oil can cause bleeding problems
>since both act to inhibit coagulation. I don't know if this is also
>true of vitamin E and aspirin in combination.

    I don't know, either.  Vitaman E interfers a bit with vitamin K
absorption, but not enough affect coagulation times in normal people.
Still, ever little bit sometimes counts when you're taking a bunch of
these things.

                                            Steve Harris, M.D.

From: B. Harris)
Subject: Re: Vitamin E, Synthetic vs Natural
Date: 9 Jun 1998 04:35:23 GMT

In <> writes:

>I've heard that synthetic vitamin E capsules are just as good as
>vitamin E capsules from natural sources. Does anyone have any input on
>this subject?
>Thanks in advance.

  They aren't.  The synthetic stuff is given an IU potency based on the
idea (from a rat model not very applicable to people) that natural
tocopheral (d,d,d) is 1.36 times more active than synthetic 8 isomer
mix (dl,dl,dl).  In the human body, however, we now know that natural
d,d,d tocopherol is retained at levels twice as high for the same dose
as the total sum of the levels of 8 isomer mix, suggesting that the all
delta or d,d,d stuff is probably about twice as potent as the 8 isomer
mix (this may be entirely due to the 50% of the dl,dl,l in synthetic
mixes which has essentially no vitamin activity at all-- perhaps this
is true because these molecules are simply not retained in tissues, or
are rapidly broken down-- we don't know).

   In any case, the "400 IU" d-alpha tocopheral is probably about 50%
more potent than the "400 IU" dl-alpha synthetic product, since the
wrong IU potency correction factor is still being used between the
products.  Unless you happen to be an E deficient pregrant rat.

   Sythetic E probably costs more than 50% more, too, however-- so
there still remains the question of bang per buck, which STILL may
remain with the dl product.  But I take only the natural d,d,d isomer
(labeled simply d), since the price differences per I.U. are not enough
to make me ingest unnatural vitamin isomers when I don't have to.
Those of us who remember the DL carnitine story probably are a little
more careful.

                                       Steve Harris, M.D.

From: B. Harris)
Subject: Re: VIT C DANGERS
Date: 27 Jun 1998 19:11:14 GMT

In <>
Ryan Maves <> writes:

>Any thoughts about the use of high-dose vitamin C and E in transplant
>patients? An hepatobiliary surgeon I've done some research with appears to
>favor this practice, but I'm fairly unfamiliar with it.

   Vitamin E is very powerful ischemia protector and free radical trap,
and is a cornerstone of our own brain anoxia studies (the trick is
getting it into the brain in time, of course).  I've no doubt it will
turn out to be useful for all other organ preservation and transplant,
where ischemic damage must be overcome for the organ to function.

   We've been leary of vitamin C, both because our model (dogs) make
their own in large amounts, and because of the nasty Fenton interaction
of C with free iron (which damaged livers, I'm sure, release in
quantity).  If I was your prof, I'd be looking more into selenium and
(especially) NAC, 2-oxothiazolidine carboxylate, and other glutathione
precursors (glutathione esters like monomethyl ester, and so on).


From: B. Harris)
Subject: Re: how much Vit E is too much?
Date: 30 Jul 1998 05:58:26 GMT

In <6potme$> "Jim Scannell"
<> writes:

>I'm cross-posting this to I've read that you should not
>have more than 400IU of vitamin E per day. I don't know what the side
>effects of too high of a dosage are but yes it is dangerous because of being
>fat soluble.

    Except that this isn't true.  Vitamin E is the only fat soluble
vitamin which has essentially no toxicity.  All reports of E's toxicity
spread like some kind of urban myth in some resports in the early
1970's, and that hasn't been seen again.  A bad batch?  I dunno.  But
studies in the 80's and 90's, even with huge doses (2000 IU a day) have
shown no problems.  People have eaten so much E they had E slicking up
their skin because it was coming out of their pores.  Still no problem.

    Not that I think that more than 1000 IU a day is likely to do
anything more for you than less.  And the amount your can absorb in one
meal definately flattens out at about 400 IU, even with a high fat
meal.  The relationship of E in your blood to E in your diet is
log linear.  It takes increasing dietary dose by 10 to get a 2 times
increase in the blood.

                                      Steve Harris, M.D.

From: B. Harris)
Subject: Re: how much Vit E is too much?
Date: 30 Jul 1998 07:54:27 GMT

In <6pp38j$> (Greg Whitman)

>My mom, who is followed fairly closely, being a 5-year-out breast ca
>patient, accidentally took a higher dose of vit. E than recommended.
>Her liver enzymes were elevated on one of the routine follow-up lab
>tests.  Coincidence?  Well her doc found the problem and got her back
>on a typical dose, and her liver enzymes normalized.  AFAIK this isn't
>an anomalous occurrence.  So vit.E isn't exactly 100% "nontoxic", unlike
>FD&C red #3 you find in crayolas.  :)

    What can I say?  This hasn't been reported in any group of E
takers.  I suppose there's always somebody out there who has a reaction
to anything.  At the same time, elevations in liver enzymes in reaction
to drugs can sometimes be ignored, and don't necessarily mean the
person is being badly damaged, or is on the way to liver failure.
Depends on the drug, depends on which enzyme (GGT, for example, is
benignly elevated by anything that induces smooth ER and P450-- eg,
dilantin, phenobarbital, etc, etc), and depends on the degree of
elevation (often 5x being the cutoff for stopping treatment, as with

                                      Steve Harris, M.D.

From: B. Harris)
Subject: Re: how much Vit E is too much?
Date: 30 Jul 1998 11:38:25 GMT

In <> (Matti Narkia)

>30 Jul 1998 05:58:26 GMT in article <6pp222$>
> B. Harris) wrote:
>>    Except that this isn't true.  Vitamin E is the only fat soluble
>>vitamin which has essentially no toxicity.  All reports of E's toxicity
>>spread like some kind of urban myth in some resports in the early
>>1970's, and that hasn't been seen again.  A bad batch?  I dunno.  But
>>studies in the 80's and 90's, even with huge doses (2000 IU a day) have
>>shown no problems.  People have eaten so much E they had E slicking up
>>their skin because it was coming out of their pores.  Still no problem.
>>    Not that I think that more than 1000 IU a day is likely to do
>>anything more for you than less.  And the amount your can absorb in one
>>meal definately flattens out at about 400 IU, even with a high fat
>>meal.  The relationship of E in your blood to E in your diet is
>>log linear.  It takes increasing dietary dose by 10 to get a 2 times
>>increase in the blood.
>Long ago someone in this newsgroup claimed that "low to medium" doses of
>vit. E are immune system boosters, but very large doses have
>immunosuppressive effects. Any truth in this?

     So far as I can tell, this is correct.  You need some free
radicals for the immune system to work.  Damp it all down, and NOTHING
happens.  Not even what's supposed to.

From: B. Harris)
Subject: Re: Natural verses synthetic vitamin E???
Date: 13 Aug 1998 06:32:03 GMT

In <> Tom Matthews <> writes:

>Jim wrote:
>> Natural Vitamin E does have better bioavailability (absorption), and
>> according to recent research is retained by the body longer than synthetic.
>Please cite peer-reviewed references for these non-standard assertions.
>Once again, half the synthetic moleclues are indentical to the natural
>ones and *must* behave the same in both absorption and retention by the
>body so long as the environment of their intake is the same.

    Well, yes.  But the latest research didn't really look at which
isomers in the 8 isomer synthetic mix were the ones responsible for the
lower (50%) tissue levels of this stuff.  We assume it's the 4 that
have the levo configuration at the chromane ring/tail junction, since
sterioisomerism here is known to screw up vitamin activity (from other
studies), but not at the other sites in the hydrophobic tail (which, I
suppose, can stick our or kink any old way in the membrane).  But
nobody really knows, at this point.  All that is known is that
deuterium-labeled molecules in the 8 isomer mix are retained only half
as well in toto, as deuterium labeled d,d,d-alpha tocopherol, the stuff
in nature.


From: B. Harris)
Subject: Re: Vitamin E Toxicity??  How Much??
Date: 2 Mar 1999 07:55:25 GMT

In <7bfu5j$> "Gary B. Modes"
<> writes:

>How much vitamin E can a person safely take each day, long term, before
>it becomes toxic? I've heard that the body can absorb and store vitamin E
>(albeit in small amounts) and that eventually, over time, a toxic level
>will occur if an individual takes too much. How much is too much?? And,
>how much does one really need each day to maintain health?? Please set
>the record straight. Thanks for you help in advance.

   Vitamin E is non-toxic at doses of at least 1000 IU per day for
years, and probably much more.  All vit E toxicity reports go back to a
couple of papers in the 1970's which claimed a flu-like reaction to 400
IU of vitamin E, with muscle pain and malaise.  But after that, this
reaction went away and has never been seen again.  Even in a number of
larger studies at much higher doses.  I conclude it was either a social
phenomenon (like syringes found in coke cans) or else there were some
bad batchs of vitamin E on the market in the 70's.

   Recently, one study used 3000 IU a day of vitamin E as a treatment
for Alzheimer's.  The rate of decline appeared to be less than in the
placebo group, though there were some problems with the initial
randomization so far as disease severity went (that should have been
stratified, but wasn't, with the result that groups started in a
non-equivalent state with regard to the important variable being
measured).  However, over several years, no toxicity in the E group was

From: B. Harris)
Subject: Re: Vitamin E Toxicity??  How Much??
Date: 3 Mar 1999 12:35:41 GMT

In <> (C. J. Fuller) writes:

>However, if you are on blood thinners like Coumadin, you should not take
>high dose (>100 mg/day) vitamin E. Vitamin E can interfere with the
>absorption of vitamin K from the intestine and could interfere with
>clotting times.

    Actually, a person taking a blood thinner should not START on E
without letting the doctor know.  And that can then be compensated for,
if the doctor has a tad of experience (it's not a large effect).  And
as or starting coumadin, there's no problem titraing coumadin to
whatever vitamin E dose you're on, provided you don't *change* it.
It's a lot easier than trying to follow people's varying vegetable
intakes, or Ensure or Boost intakes (which both contain, damn them,
vitamin K).

From: B. Harris)
Subject: Re: Vitamin E Toxicity??  How Much??
Date: 4 Mar 1999 10:15:19 GMT

In <01be65df$43f51480$96db0ad0@doc-s> "Immaterial" <>

>Texts such as _The Nutrition Desk Reference_ and _Perspectives in
>Nutrition_ place the limit at 800 i.u./day.  Long term usage above
>that level creates toxicity.

   I'd be curious as to what these seconary sources cite in the primary
expermental literature to back that claim.  Can you supply any of their
references?  All knowledge comes down to experiment or epidemiology.
How do THEY know 800 IU of E is toxic?  What makes THEM think so?

>True whole Vitamin E (not to be confused with the antioxidants - the
>alpha, beta, gamma, and delta tocopherols - which comprise its shell) can
>be quite adequate at levels below 40 i.u./day. However, this fact is
>little known or understood within the medical research community.

    Um, that's because the above is nonsense.  Alpha, beta, gamma, and
delta tocopherols are simply molecules with vitamin E activity.
"Vitamin E" is not one thing, any more than most vitamins are.  It's
the name for a group of compounds (called, technically, vitomers) which
all perform a certain biological function.

> Of the shell
>tocopherols, it has been found that the best results are achieved at
>200 i.u./day, and that 600 i.u./day produced less favorable outcomes
>in the research studies.

    That depends on the research study, what the outcome being measured
was, and so forth.  Vitamin E does seem to have somewhat biphasic
action.  Doses up to a couple of hundred IUs a day are
immunostimulatory (at least for cell mediated immunity), while doses
above that are slightly immunosuppressive (helpful in inflammatory
conditions, sometimes, but obviously not helpful for infections).   But
all of this is not suprising for an antioxidant. Oxidation/inflammation
can be helpful in both healing and fighting infection.  Antioxidants in
the body are in balance, and how much you need depends on your age,
your genetics, and your particular problems (stressors).  There are no
easy answers, and many tradeoffs are involved.

From: B. Harris)
Subject: Re: Vitamin E Toxicity??  How Much??
Date: 4 Mar 1999 11:22:11 GMT

In <> "physical (Droll Troll)"
<> writes:

>Hogg's Version of Vit E:
>	The debate on the activity of alpha-tocopherol vs. the diversity
>of the whole E group is interesting, and I hesitate to go into all the
>detail.  But since some of it is a really neat example of orgasmic
>chemistry in action, maybe it's worthwhile, esp. since you won't find
>this in any nutrition texts.

    <g>  Fer sure.  But don't expect to get away without critisism.

>Why E is so nontoxic.
>	E is like a fatty acid that can't be metabolized.  So it doesn't
>do anything except sit in membranes, soaking up free radicals. Simple as
>that. It seems that E is hard-pressed to even be excreted, altho my
>theories on this are a little torturous.

   I think you reach equilibrium when the E you absorb is balanced by
the E in the sebum coming out of your pores.  There have been reports
of people whose skin was slick with the stuff.  All that being said,
there are many animal life span studies (Tappel, etc) where a life time
of E had no effect, one way or the other.  So the animals had to get
rid of it somehow.  Seriously, there are gluconuridated metabolites
which have been identified in urine.  And heavily loaded E-laden cells
are sloughed into the gut.  It wouldn't surprise me if E gets into bile
and fails to undergo enterohepatic circulation in individuals whose gut
cells have too much of it, and is thus eliminated.  All a bit like the
zinc story.  Many mysteries here, but the life time feeding studies
provide the main clue.  You do get rid of it, even if we don't know all
the mechanisms.

>	However, vit A at high levels _greatly_ fluidizes membranes, and
>in fact A and E are thought to "neutralize" each other from a membrane
>POV, such that E is somewhat of an antidote for excess A.  Or vice
>versa. Anyone taking 25,000 IU of A, as I often do, can probably take
>E virtually ad libitum.

   Too much vitamin A has some inflammatory characteristics, which
anyone who has been on Accutane (a vitamin A derivative with some of
the same side effects) can attest to.  Dry skin and dermatitis
(erythema, rash, scaling, peeling), with lips hit worst, cerebral
edema, anemia, liver necrosis and enlargment, fatigue, fever, nausea,
weight loss.  All of these resulting probably from an excess of one or
more of the hormonal metabolites of vitamin A.  One of these is a
differentiation regulator called retinoic acid, which promotes cell
growth.  In the skin the growth is apparently a bit too exuberant.

   The treatment for vitamin A toxicity is steroids and inflammatory
suppressors.  Vitamin E is one of these, and it may be acting to
counteract vitamin A toxicity (which it does in animals, to some
degree) by simply shutting down inflammation.  But not all of E's
effects on A metabolism are counter-regulatory.  Vitamin E is A
sparing, since it quite specicically prevents oxidation of A in the
liver-- so if you're OD'd on A, the last thing you want is a lot of E
keeping you from getting it out of your overloaded liver.  Moreover,
vitamin E actually exacerbates the toxic testicular derangements caused
by hypervitaminosis A (Ann. N.Y. Acad Sci. 355: 109-19, 1980).  So
watch those `nads, Hogg.  You can take all the E you want, anyway, but
all the E in the world won't protect you completely from A.

>How E protects cells
>	The "tail" of E embeds in membranes, leaving the conjugated
>"business" end (aromatic ring) stuck right on the surface (inside and
>outside) of cell membranes. The "activity" of this ring follows the rules
>of substituent activation of aromatic ring systems by methyl groups.
>alpha is most activated, beta, gamma and delta successively less so. It
>is amazing how textbook this is. So from an activity POV, alpha
>tocopherol is the "E of choice", altho in foods, gamma tocopherol is most

    But a major function of E may be to react with certain free
radicals, one of the nastiest being peroxynitrite .ONOO- which is the
adduct of .NO and .O2- (nitric oxide and superoxide).  And only the
gamma does this well, for reasons still not clear, but seen
experimentally.  Aromatic ring electrophilic attack activation rules
don't predict affinity in free radical reactions.  Indeed, the
antioxidant properties of the tocophrols are not in the same order as
their vitamin activities.

>	Other antioxidants, like Vit A, beta carotene and caretenoids and
>lycopenes, etc., have their business end in their "tails", where they
>can't quite do anything until it's "too late", membrane-wise.  Thus,
>vit E is the lipid first line of defense, while Vit C is the aqueous
>first line of defense.

   Sounds reasonable.  Though again, the affinities of these molecules
depend on the thing being trapped.  Carotenoids, for example, deal best
with singlet oxygen, which isn't even a free radical. The entire
congugated bond system here (most of the molecule) is the "business

                                         Steve Harris, M.D.

From: B. Harris)
Subject: Re: Vitamin E Toxicity??  How Much??
Date: 5 Mar 1999 14:36:05 GMT

In <> "physical (Droll Troll)"
<> writes:

>E and A interaction toxicity:
>	Your point is well taken, and I should have separated A's toxicity into
>its membrane toxicity and its receptor-mediated (chemical) toxicity. I
>think the key here is which comes first, or is the more dominant
>effect.  Electron microscopy studies of toxic levels of A show
>unambiguous organelle membrane rupturing from A overdose, with the
>implication of subsequent cell death.  I don't know, however, if this is
>the dominant toxic route.

   I would guess not, as the damage is far two stereotypic in space in
the body.  The skin of the palms of the hands comes off, presumably due
to larger sheer stresses there. But not all organs are affected
equally, or even close.

>	E in sebum is fascinating!  Maybe that's why my cats are always
> washing me!

   Nah.  They like salt and butyric acid.  Shower more.

>	Just a note on A:  retinoic acid is more toxic than retinol
>because they have distinctly different receptors, with the RA receptor
>orders of magnitude more active than the retinol!  Apropos of
>regulation discussed in another thread, this is why introduction of RA
>is dicey in itself.
>Interestingly, these receptors, along with D receptors, are
>nuclear-membrane bound, with all that that implies.

   Yes, and steroid and thryoid receptors-- they're all the same
mutated gene.  Interestingly, although there are such receptors for the
retinol, it's not too important, because you can do without it, except
in the eye.   Animals can make retinoic acid from retinol but not the
reverse.  Feed them only retinoic acid and they are perfectly healthy
(including their corneas which do NOT dry out), but soon totally blind
anyway, from retinal rod and cone degneration.

>You said:
>	(1) Aromatic ring electrophilic attack activation rules
>> don't predict affinity in free radical reactions.
>	(2) Indeed, the
>> antioxidant properties of the tocophrols are not in the same order as
>> their vitamin activities.
>	But these rules _do_ appear to correlate with the vitamin activities,
>with a stereochemical question mark between the beta and gamma.
>	I'm not sure I follow the distinction between (1) and (2) above.

    Okay.  Molecules like .O2- which want an electron from a pi bond on
the ring (leaving the other bond electron to find its way to a
substituent oxygen atom, which being a diradical, takes it in), act
much more like H+ (a classic electrophile) than like Cl:- , a classic
nucleophile.  Alkyl groups which donate e- and increase electron
density in the ring should in theory make them more susceptable to
reaction wtih .O2-.   Except they don't, experimentally. Yet the more
methyl groups, the better their vitamin activity.  So it's all screwed
up.  That was my only point.

>	Your point about gamma-E is very interesting, if true!If true, it
>points to a stereochemical effect, rather than an activating one, as
>both alpha and beta are much more "active".

   Are much more active in the fetal rat resorption model.  What this
has to say about aging, if anything, is anyone's guess.  I'd put my
money on the stuff which actually is shown to work.

>	Anyway, it looks like I got off rather easy on this one, unless
>your bedside manner has been improving.  Patch Adams, perhaps?

    No, Forrest Gump, Rain Man, and The Doctor. The year of lovable
brain damaged men is gone at the movies (unless youc count Costner) and
we now start into the mythos of brain damaged women (no smart remarks,
please).  I figure more pepul will be nice to me if Im not two smart.

                                       -- Charlie

From: B. Harris)
Subject: Re: Vitamin E supplements may cause harm??
Date: 31 Mar 1999 11:23:36 GMT

In <> Tom Matthews <> writes:
>F. Frank LeFever wrote:
>> Thank you, Dr. Harris!  I have come to rely upon you for really sound
>> comment.  Serendipitously, when I replenished my Vit. E supply this
>> evening (from the Vitamin Shoppe chain, using their brand), I noticed
>> that in addition to d-alpha (which I get preferentially, rather than
>> the more usual and cheaper dl-alpha), I noticed that it had a mix of
>> related tocopherals, gamma among them.  Any data on the others?
>> Probably no data on optimal mixes, if research based on pure d-alpha...
>Here is one of the prime abstracts which suggests the benefits of
>supplementing adequate gamma tocopherol along with your alpha.

    It's the only abstract.  And it's a paper done on stuff in a test
tube.  So let's not go overboard.  Just for example: we don't even know
if .NO derived damage to fats in peroxysomes is important in the
pathogenesis of your average cause of atherosclerosis.  There are many
other ways to make free radicals than to start with .NO, or use .NO..

From: B. Harris)
Subject: Re: Aspirin or Vitamin E?
Date: 22 May 1999 06:39:35 GMT

In <7i3inn$31q$> (Jim)

>Is there any consensus on the relative merits of Vitamin E versus
>Aspirin to prevent heart attacks? As in, which is more effective?
>Should one use one or the other but not both? Any feedback is

  Each cuts risk of a second heart attack by roughly 50%.  No study has
looked at them together, but they surely work by different proximate
mechanisms (ie, where they start work on platelet function).  Whether
they end up working by the same endpoint mechanism, or whether their
effect will be additive, synergistic, or perhaps even (for some odd
reason) antagonistic, is not known.

   If you must choose one or the other, choose E, in that it is less
dangerous (in the PHS, there was a statistically significant increase
in GI bleeds serious enough for hospitalization, even on low dose
aspirin, ie, one tab every two days).  I think a men over 40 and women
over 50 should especially consider one or the other, and for those who
have any risk factors at all, it would be entirely reasonable to take
both.  If you take aspirin, it would also be reasonable to cut your
major bleeding risk by partly blocking stomach acid production with
Zantac or Pepcid.

From: B. Harris)
Subject: Re: Vitamin E type/clinical trials
Date: 29 Dec 1999 09:04:32 GMT

In <84bc9f$jgp$> Dr. S. <> writes:

>Perhaps this will be a portion of your answer:
>The original published study paper may or may not have identified the
>type or brand of vitamin E; still, I'd look there first.  If the study
>was negative about vitamin E, check to see if they used enough (several
>hundred International Units daily, at least) and if they used natural
>vitamin E (*d-alpha* tocopherol, and not dl-alpha, the synthetic


  The dl-alpha is just one synthetic form, for there are lots of
d-alpha semi-synthetics.  Nowadays, "dl" usually means actually
dl,dl,dl-alpha, which means *completely* synthetic.  Once upon a time,
there really was a dl,dd,dd-alpha tocopherol which was semi-synthetic,
which had about the same activity as today's "dl" which is the totally
synthetic all racemic dl,dl,dl form.  This is counterintuitive, but
results from the fact that d,l isomerism about the other two (last two)
chiral centers doesn't affect vitamin activity or body retention much.
It's that first chiral (mirror) center, where the chroman ring attaches
to the tail, that screws things up, if it's the "l" and not the "d"
form (RRR as opposed to SRR-alpha).

  When you buy "d-alpha" tocopherol (d,d,d or R,R,R) you're getting a
product which is about 80 to 100% semi-synthetic, having been made by
methylation from gamma (and sometimes delta) tocopherols.  But it's
identical to the natural alpha tocopherol, insofar as it's pure (which
it isn't, of course-- who knows what the side reaction products are,
and how they get taken out, or if they do?  I don't).  But you can't
get the pure d-alpha stuff extracted from oil, no additional chemistry
done, in a capsule, anyway.  It's just not available on the market, for
that particular compound. The words "all natural," as we ought to know
by now, mean absolutely nothing.  You're lucky if they mean even that
you're getting no l-alpha tocopherol.  They certainly never mean you're
getting no synthetic tocopherol.  You have to read the label and hope
it's telling you the truth, even to get as far as knowing you're
getting no l-alpha.  What else you're getting, you never know.

                                  Steve Harris, M.D.

From: Steven B. Harris <>
Subject: Re: Please answer my 2 1/2 questions.
Date: Sat, 03 Mar 2001 04:31:40 GMT

In article <H3kn6.3429$>,
	"Baron Blackfang" <> wrote:

>The abililty to rotate polarized light makes the compound a stereoisomer.
>Many biochemical pathways require that a compound possess the ability to
>rotate polarized light in a particular way for optimal effectiveness in a
>While natural chemicals have the correct stereoisomer, synthetic
>chemicals are often of the wrong stereoisomer and may not be as

May not or may-- it depends on the chemical. Your body converts D
methionine to the L form, for example, so either is effective.  The
natural vitamin E is RRR, but the body uses SRR, SSR, and RSR just
fine. Only the RRS is ineffective, so the 8-isomer mix still has 75%
of the activity of the natural product.

As for synthetics being the wrong stereoisomer, that depends on who
does the synthesis. Most of the RRR-alpha vitamin E (what's called
"d-alpha on bottles) is actually synthesized. Some of it totally
sythesized from base petrochemicals, some of it by methylation of the
gamma and delta RRR vitamin E's in oils. But it's all d-alpha
tocopherol on the bottle. You always know dl-alpha is semisythetic,
but these days you can't tell a thing about the d-alpha except that
it's *probably* synthetic. I know of no completely naturally
extracted and not at least semi-synthetic 400 IU vitamin E on the
market. Saying "natural" on the label means (as we know) legally not
a damn thing.


From: "Steve Harris" <>
Subject: Re: Gamma tocopherol, the liver ...
Date: Sun, 17 Feb 2002 18:09:48 -0700
Message-ID: <a4pkkq$81e$>

"Quentin Grady" <> wrote in message
> G'day G'day Folks,
>  When supplement manufacturers turn out "natural" alpha tocopherol
> they frequently have converted some gamma tocopherol to alpha
> tocopherol.  They are allowed to do this because their source of
> tocopherol was natural.  Of course you might ask why do they do this.
> Alpha tocopherol is thought to have a higher efficacy than the other
> tocopherols.


It does have higher vitamin activity.  But that's not why manufacturers buy
alpha-tocopherol ("alpha-T") which has been converted from gamma-tocopherol
("gamma-T") to put into "Vitamin E" pills. The reason in the US (at least)
is because you're only allowed to report vitamin E activity on bottle labels
in IUs based on alpha-T content.  Even though there is a perfectly good
conversion to IUs from gamma-T.

> Much of this supposed superiority is based on the
> knowledge that most other tocopherols are removed on their first pass
> through the liver. The usual assumption is that the other forms are
> therefore largely a waste of packaging space.


One wishes it were this sophisticated. You give the FDA too much credit.
Also, your facts are not in evidence.

Gamma-T in single doses in a healthy individual who is vitamin E replete,
does indeed get (mostly) metabolized almost immediately (within a day) and
go to metabolites which go off in the urine (things like
gamma-CEHC-gluconuride).  However, please don't infer from that that this is
what happens to all gamma-T you take. There are pools of gamma-T in the body
which are doubtless MUCH slower, and there must be exchange in and out of
them. I know of no long term gamma-T supplementation studies in humans to
explore that, but in rats where you can supplement depleted animals, it
takes tissues stores several *weeks* to get to max gamma-T content.  That
means gamma-T has a very slow compartment in rats. If it didn't in people
(and a much slower one than in rats, since our metabolisms are 1/5ths as
fast) I'd be very surprised, since gamma-T's distribution is very similar to

Now, there are differences between alpha and gamma-T metabolism. Levels of
gamma-T in tissues run at much lower absolute levels (like a fifth of those
of alpha), due to the fact that the binding and transfer proteins for vit E
are specific to alpha-T, and store it by binding it, and sticking into
lipids preferentially.  However, here again you could be fooled by even
alpha-T, if you just looked at plasma levels. For example, if you give
whopping doses of alpha-T to humans (this has been studied) for some time,
it takes maybe 5 days to hit max blood levels (about 2x normal at a dose of
10 RDIs), and then decays away in 2 weeks when you stop. However, levels of
alpha-T in fat tissues take more than a year equilibrate to a new dose,
implying half-times of many months, so you can see that the simple blood
picture isn't a good marker for metabolism or compartment half-times for
this vitamin. It probably isn't for gamma-T either, based on the repletion

The transfer/binding protein for alpha-T makes it metabolize a bit like
vitamin A, where you only start seeing funny metabolism only after the
retinyl binding protein system has been saturated. When that happens for the
alpha-T binding proteins you start to see alpha-CEHC urine metabolites from
alpha-T that remind you a lot of the gamma-T paths. Again, though, just
because this doesn't happen with gamma-T, that doesn't mean all gamma-T is
immediately metabolized.  It just means that overdoses or large doses are.
For alpha-T, by contrast, there's a buffer before you get spillover
metabolism to water-soluble metabolites. Your body's preferentially trying
to hold on to alpha-T, which probably tells you something.

There are suggestions in the literature that gamma-T might have some helpful
body function that alpha-T doesn't, but there's not much gross evidence for
it. Gamma-T's a much better anti-inflammatory, but that doesn't mean you
can't raise perfectly healthy animals on alpha-T alone, which live to ripe
old ages (they live as long as on mixed diets, which contain mostly
gamma-T). You can. Thus, there is no direct and strong evidence yet that
gamma-T is necessary for health.

You might wonder what happens when you try to raise animals on gamma-T alone
and no alpha-T, and the answer is that you can't do it. If you try, even
after many generations you get healthy animals, able to reproduce, whose
bodies contain some alpha-T (though not at normal levels). Evidently there
is a metabolic path, not yet elucidated, that turns gamma-T to alpha-T.  So
(if they have to) animals are able to methylate the gamma up to alpha, just
like pharmaceutical companies do!  Probably your own body can do this also.
Biochemically ones suspect for obvious reasons that this will turn out to be
yet one more B-12 dependent reaction.


From: "Steve Harris" <>
Subject: Re: Oxidation/polymerization of polyunsaturates (was Re: alpha lipoic 
	acid eliminates wrinkles?)
Date: Sat, 9 Mar 2002 09:25:38 -0800
Message-ID: <a6dgh7$c9m$>

Uncle Al wrote in message <>...

>Oil-soluble vitamins are inefficiently excreted.  OD on Vitamin E
>leads to blood clotting disorders and visual impairment (competition
>with Vitamin A).

Nah.  There's been large studies of E at doses of 1600 IU a day (the
Alzheimer's prevention studies) for several years.  Nobody had problems with
clotting or vision. This is a theoretical problem but only in people who are
very marginal in vitamin K status, and in practice that takes Coumadin.
Even then you can compensate for vitamin E taking, so long as the patient
doesn't change routine.

Vitamin E is oil soluble but doesn't behave like it in excretion. If you
take a lot, the excess is rapidly converted to water soluble metabolites
which are conjugated with gluconate by the liver, and excreted in the urine.


From: "Steve Harris" <>
Subject: Re: Oxidation/polymerization of polyunsaturates (was Re: alpha lipoic 
	acid eliminates wrinkles?)
Date: Sun, 10 Mar 2002 20:09:52 -0700
Message-ID: <a6h78o$o4h$>

"DB" <> wrote in message
> Steve Harris wrote:
> > Vitamin E is oil soluble but doesn't behave like it in excretion. If you
> > take a lot, the excess is rapidly converted to water soluble metabolites
> > which are conjugated with gluconate by the liver, and excreted in the
> > urine.
> Interesting. Above what amount of vitamin e is an 'excess.'?

Apparently anything over a few 10's of mg a day.  But again, remember that
for the d-alpha tocopherol (but not the gamma or delta) you need to saturate
your body's alpha tocopherol binding protein stores before you start
excreting the extra quantitatively.  If you start taking 400 IU a day it
takes a couple of weeks before you're excreting that much a day. For the
gamma or delta vitamers, the balance between ingestion and excretion happens
much more rapidly.


From: "Steve Harris" <>
Subject: Re: Oxidation/polymerization of polyunsaturates (was Re: alpha lipoic  
	acid eliminates wrinkles?)
Date: Sat, 9 Mar 2002 09:10:12 -0800
Message-ID: <a6dfp3$5h1$>

DB wrote in message ...

>Actually there are 800, 1000, and 1500 IU softgels available on some store
>shelves. I take around 1000 IU natural E and 200 mg gamma E. Generally
>speaking, the more supplements one takes the better, imo. Call it a hunch
>based on a shitload of animal data.


What animal data is that?  Decades of trying to get animals to live longer
by supplementing them with vitamins has generally been a total failure. They
don't live as long at 1/2 RDA, but it's very hard to see difference between
RDA and 2x RDA (or RDI or whatever the current obfuspeak is these days).
Poor Tappel has done those vitamin E/life span studies several times.
Results: nada. All these things protect well against certain free-radical
damage in lab assays. How that translates to real life isn't clear.  And
what the dose needed isn't clear.


From: "Steve Harris" <>
Subject: Re: EU vitamin ban -can cutting vitamin intake be dangerous?
Date: Sat, 23 Mar 2002 13:56:31 -0800
Message-ID: <a7itka$aeq$>

Tom Matthews wrote in message <>...

>I have no idea why you continue to insist that such scenarios are "more
>likely". Not only do the various E vitamers have seriously different
>effects, but there is excellent evidence to support their
>interdependence (not to mention their relationships with other vitamins
>and nutrients).


I think "interdependence" is a strong word and probably a bad and misleading
word for lack of total pharmacokinetic and pharmacodynamic independence.
Very few things have total pharmacologic independence, and good examples are
interactions between metabolism of numerous man-made drugs and various
nutrients. Levels of some go up, others down when the vitamin is given in
large amounts. None of which mean in the least that evolution has designed
in some "interdependence" of these things-- obviously for man-made drugs
this is not the case. But similar such findings are used to support supposed
interdependence of E vitamers. That's bad reasoning.

There is an alpha tocopherol binding protein which picks this vitamer up
preferentially, suggesting that this is the one the body prefers. There is
NO evidence that the body needs any other vitamer.  There are no deficiency
symptoms or signs or any other problems known in animals not getting the
other vitamers. Life span studies done by myself and many other researchers
show perfectly normal life span studies with alpha tocopherol primarly (and
for that matter, these studies have classically been done with the dl,dl,dl
8-isomer mix, only one of which is found in nature). Possibly the animals
also get some gamma from the corn oil typically used in them as fat source,
but it's not much. The life span controls for these studies are those
historical studies in the pre-chow era, in which animals got mixed food
diets, where the E is mostly gamma-E.  Life span's weren't any better, and
were usually worse.

We know from the reproductive studies that any active E vitomer is able to
substitute for any other, to the limit of delectability of pathology. One
study has been done in which animals were raised for 3 generations on
nothing but gamma-E.  They did fine, but apparently were able to convert
some gamma to alpha-E.  Again this suggests that alpha-E is what the body
prefers (for storage if for nothing else).  That's it.  Claims for a
specific nutritional need for gamma-E or tocotrienols rest on test tube
science or shaky post-hoc epidemiology, all of which are always insecure, to
say the least.  Frankly I don't believe them, due to the gold-standard
semi-synthetic diet life span study results.

>Of course, "there is no free lunch"! One cannot willy-nilly simply take
>large doses of any one particular vitamin or nutrient without some
>downsides! *Everything* has a U shaped dose/effect curve. To use a
>phrase that I learned from you: "the dose makes the poison".  However,
>this does not preclude the possibility of beneficially taking a selected
>combination of vitamins and nutrients at above food obtainable levels,
>by intelligently reading the research and using it to guide one's
>choices. To think that such is not possible (as you appear to do) is to
>embrace an extremely negative, pessimistic and cynical world-view (which
>you again appear to do - perhaps because of your own advancing age and
>declining physical condition - I hardly recognized your new picture.
>BTW, a little CR would help you a lot.).

No, now, ad hominem.  Yes, nearing age 45 I've certainly lost my boyish
charm (unlike you, "Tom," who at age 45 were no doubt still being mistaken
for 25.  Not). Today's newsflash: that tends to happen to us humans (take a
look at Bill Gates, Michael J. Fox, Pearson and Shaw, and basically most
people of average genetics who haven't had plastic surgery). No, I don't
like it. And yes, in fact, I am on a diet.  And no, I refuse to dye my hair
or have a facelift. Graying hair is not fixable with nutrition; the
middle-age spread of course is.  But it's also mostly cosmetic and low
levels. My physical condition is fine. I know because I'm not dead, having
recently subjected my body to learning scuba.  This is not tropical
paddling, but diving in the West coast Pacific, to depths below 100 ft, in
water at depth around 60 F (15 C).  Lots of fun, but (by the way) a place
where you're glad for every pound of extra fat-- it's not going to be nearly
as much fun when I'm skinnier. Caloric restriction (CR) may be great if you
want to sit in a nice climate-controlled lab basement or a sealed controlled
experiment in some warm place like Biosphere II.  However, In other places--
on top of a mountain in the snow, under a lot of cold water in the Pacific,
or with a nasty infection-- you may well pay a price for CR that you hadn't
counted on.  That is why I'm particularly watching you restricted Canucks--
the first one of you that crumps from infection is going to be editorialized
by moi.  If I die first of a heart attack you can do the same for me, but
don't hold your breath-- my numbers are perfect.

>*That* is what we are arguing may well be possible today and, in fact,
>has some reasonable amount of evidence in its favor. And neither you nor
>anyone else can express more than an *opinion* that we are wrong.

That it's my "opinion" goes without saying. But burden of evidence is on
you, not me. I've given you my reasoning.  The gold standard in experimental
gerontology- failing actual human trial results-- is mammalian life span
studies using long-lived strains.  Vitamin-wise, they don't argue for your
side, but mine.  So far as CR goes, rodent studies argue for your view in
controlled conditions, and primate studies are on-going (too early to tell;
biomarkers look good, but they too are being pampered).  I think the jury's
still out for the real world and humans. You may well be right. Or you may
well be wrong. Again, I have little doubt that we're in for a lot of CR
people dying of funny diseases, while all the while their compadres are
saying "Well, if it wasn't for THAT freak thing, he'd have gotten to 150!"
But that's not the way it works.  In the real world, there's a U-shaped
survival curve for body mass index, too, and it's not where CR would
predict.  CR's advocates have a lot of explanation for that (ho hum-- maybe
enough vitamins weren't being taken; that's what life-extenders ALWAYS say),
but butt they remain ad-hoc apologias for now.  I believe some of them, and
others not.  I retain skepticism also.  I've seen a lot of great theories in
medicine go down the tubes, and others succeed. Which was going to succeed
was by no means obvious, until the final results were in.


I welcome email from any being clever enough to fix my address. It's open
book.  A prize to the first spambot that passes my Turing test.

From: "Steve Harris" <>
Subject: Multivitamin Scares. (was Re: How about supplemental calcium??)
Date: Mon, 5 May 2003 16:09:30 -0700
Message-ID: <b96qvf$mjq$>

"David Rind" <> wrote in message
> Walter E. wrote:
> > I read the recent story (and the thread in this NG) regarding the
> > dangers associated with excess vitamin intake.
> > 
> > I am a 74 yo male. I told my wife "I told you so" and I stopped taking
> > my worthless One-a-day vitamins. Needless to say that we eat a well
> > balanced diet with lots of fruit and vegies. We are reasonably
> > healthy.
> > 
> > Now, what do I do with the calcium supplement pills that have been
> > foisted on me for years? Is there any valid reason for routinely
> > chewing calcium tablets? Am I going to collapse in a boneless heap if
> > I stop taking extra calcium to the tune of 1500 mg a day?
> >
> I didn't read the recent thread in this ng, but while there are reasons
> to be cautious about certain vitamins (particularly vitamin A, both as
> beta carotene and retinol for somewhat different reasons), I don't think
> going to the other extreme of "all vitamin supplements are worthless or
> harmful" is justified by the evidence.


Hear, hear. We recently got a spate of amazingly stupid
anti-multivitamin articles, based on just two very small
pieces of evidence:

1) Pre-formed vitamin A is more toxic than we thought, with
problems occurring in supplementation very near the RDI
2) Vitamin E supposedly increases stroke risk.

The first is interesting but old news, in a sense. We all
knew pre-formed retinyl palmitate type vitamin A supplements
were not that great an idea, and that is why the best
supplements (Twinlab Daily One, for example, which I take)
have the A as beta-carotene. There are large safety studies
on beta carotene, and it's not dangerous except possibly in
smokers. The body makes only as much retinol out of beta
carotene as it needs, and retinol bone toxicity does NOT
occur with beta carotene. There is some evidence that
beta-carotene may influence the risk of smokers getting lung
cancer, possibly through it's conversion to retinoic acid, a
growth factor for epithelial cells and perhaps a cancer
promoter. Vitamin-wise I think smokers would be smarter to
supplement with B-complex and C only.

The stuff about vitamin E and stroke qualifies are nearly an
outright lie. ONE study from Finland has found a risk in
smokers ONLY of combination of antioxidants related to
stroke-- any they had slightly more of ONE TYPE of stroke,
the hemorrhagic type stroke, but made up for it by having
fewer of the thrombotic type. Overall, antioxidants seemed
to be positively affect risk of total stroke in those at
risk for stroke (not only smokers). Thus, smokers with high
blood pressure at risk for the hemorrhagic type stroke might
think about avoiding E supplements (this is megadose E here,
not the amount in the usual one a day vitamin). But we can't
even say that for sure. Vitamin E reminds one of aspirin,

The very best quality evidence we have for the effect of
megadose (400 IU) vitamin E on stoke and other
cardiovascular endpoints, is the large randomized
prospective placebo control HOPE trial.  In that trial,
vitamin E flunked out, with no effect on any cardiovascular
endpoint, either positive OR negative (including in the
smokers). This was rather surprising in view of the
epidemiology (high blood levels of E are epidemiologically
associated with low stroke and cardiovascular risk), but at
least HOPE shows once and for all that vitamin E even in
megadoses can't be very dangerous.

So there you are. Take your multivitamin, so long as it has
only beta carotene for the A and no retinyl palmitate.  If
you're a smoker, don't take vitamin A supplements of any
kind, including those in multivitamins. If you smoke, you
might consider the all-B-with-C type vitamin, with a
multimineral. Whether or not an extra vitamin E pill will
hurt or help you is up for grabs.

Steve Harris, MD

From: David Rind <>
Subject: Re: Multivitamin Scares. (was Re: How about supplemental calcium??)
Date: Sat, 10 May 2003 16:54:30 -0400
Message-ID: <b9jouu$47s$>

Steve Harris wrote:
> The first is interesting but old news, in a sense. We all
> knew pre-formed retinyl palmitate type vitamin A supplements
> were not that great an idea, and that is why the best
> supplements (Twinlab Daily One, for example, which I take)
> have the A as beta-carotene. There are large safety studies
> on beta carotene, and it's not dangerous except possibly in
> smokers. The body makes only as much retinol out of beta
> carotene as it needs, and retinol bone toxicity does NOT
> occur with beta carotene. There is some evidence that
> beta-carotene may influence the risk of smokers getting lung
> cancer, possibly through it's conversion to retinoic acid, a
> growth factor for epithelial cells and perhaps a cancer
> promoter. Vitamin-wise I think smokers would be smarter to
> supplement with B-complex and C only.

The risk in smokers may not be only for cancer. At least one
of the large trials of supplementation found an increased
risk of cardiac events when beta carotene was given for
secondary prevention of CHD, and one primary prevention
trial also found an increase in cardiac events (though
other primary prevention supplementation trials did not).

David Rind

From: "Steve Harris" <>
Subject: Re: Good vitamin E vs BAD
Date: Fri, 16 May 2003 21:46:07 -0700
Message-ID: <ba4f51$spl$>

<> wrote in message

> On Thu, 15 May 2003 10:32:33 -0700, in you wrote:
> >
> >"Trouser Puppet" <trouserpuppet@aol.comadieu> wrote in
> >message
> >> There seemed to be allusions to some vitamin E being bad for one.
> >
> >
> >No good evidence that vitamin E supplements are harmful.
> Where did you look?  there is plenty of evidence

Ball's in your court. HOPE trial says otherwise.

       Prev Cardiol 2003 Spring;6(2):85-90

Treatment of atherosclerosis in the new millennium: is there
a role for vitamin E?

Meagher EA.

Center for Experimental Therapeutics and Department of
Medicine, University of Pennsylvania, Philadelphia, PA

Oxidative stress appears to be of fundamental relevance to
diseases as diverse as atherosclerosis, cancer, and
Alzheimer's disease. Observational data in humans have
suggested that antioxidant vitamin intake is associated with
reduced cardiovascular disease. Animal studies are largely
consistent with the concept that dietary supplementation
with antioxidant vitamins reduces the progression of
atherosclerosis. However, recent prospective, controlled
clinical trials of vitamin E, including the Cardiovascular
Disease, Hypertension and Hyperlipidemia, Adult-Onset
Diabetes, Obesity, and Stroke (CHAOS) study, the Heart
Outcomes Prevention Evaluation (HOPE) trial, Gruppo Italiano
per lo Studio della Sopravvivvenza nell'Infarto Miocardico
(GISSI)-Prevenzione trial, the Secondary Prevention with
Antioxidants of Cardiovascular Disease in End Stage Renal
Disease (SPACE) trial, and the Heart Protection Study (HPS)
present a confused picture. The various possibilities that
have been advanced to explain this discrepancy are discussed
in this review. A striking feature of these and other trials
of antioxidants is the absence of a biochemical basis for
patient inclusion or, indeed, dose selection. Patients with
high levels of oxidant stress or depletion of natural
antioxidant defense systems may be the most likely to
benefit from antioxidant therapy. If this is the case, then
reliable, quantitative indices of in vivo oxidant stress
such as urinary isoprostane levels should be considered as
an inclusion criterion for patient selection. Future trials
of antioxidant therapy in cardiovascular disease should then
be targeted toward such patients with high levels of oxidant
stress or patients with depletion of natural antioxidant
defense systems. Furthermore, the dose of antioxidant should
be chosen based on a surrogate readout that is a reliable,
reproducible, and easily obtainable in vivo measure of
oxidant stress. In the interim, although the safety of
vitamin E up to doses of 800 IU/day has been determined, the
conflicting nature of the results published to date
encourages us to avoid making premature recommendations with
respect to vitamin E supplementation in the prevention and
treatment of cardiovascular disease. Copyright 2003 CHF,

PMID: 12732794

From: "Steve Harris" <>
Subject: Re: How important is gamma tocopherol?
Date: Tue, 1 Jul 2003 12:26:38 -0700
Message-ID: <bdsn9f$blf$>

"M. Schwartz" <> wrote in message
> I've read that large amounts of alpha tocopherol displaces critically
> important gamma tocopherol in the cells. Also stated in the article was
> while alpha tocopherol inhibits the production of free readicals, it is
> the gamma tocopherol form of vitamin E that is required to trap and
> neutralize existing free radicals. So, could the reason some studies
> show no benefit of taking vitamin E be due to no gamma tocopherol or not
> enough gamma tocopherol?
> Mel



The role of gamma in normal nutrition is up for grabs.
Clearly alpha is the most "vitamin-like" of the tocopherols,
inasmuch as it has a specific binding protein which doesn't
like gamma (so alpha has a storage reservoir), and your body
converts gamma to alpha to give you some, even if you get
nothing but gamma in your diet, which means it's alpha that
your body really wants bad. So the body definitely needs
alpha for some function, and probably nothing else will do
for that function (gamma acts there only as a pro-vitamin).

So far as the converse, it's perfectly possible to raise
generations of healthy animals on nothing but alpha, and
they get depleted of gamma on this, since they can't and
don't make gamma from alpha. No consequences are of gamma
free diets are detectable (most life span studies are
actually done on such diets, and the animals outlive natural
diet animals), which you'd think there would be some horrid
syndrome associated with loss of some vitally important

Of course, gamma deficiency is unlikely to occur in nature,
since most Vit E out there is gamma. The only gamma
depletion likely to occur is in artificial diet studies
where only alpha is fed (again, this is the norm in
semi-purified lab rodent diets). And perhaps there is
relative gamma depletion in in humans taking a LOT of alpha.

We simply don't know the consequences of any of this. From
the animal studies, we can't see any, and I will hazard a
guess that the gamma form isn't going to be that important
for overall human health and longevity, any more than it
appears to be, in rodent longevity studies using alpha-only
semi-purified diets. But of course I can't be sure.


From: Steve Harris <>
Subject: Re: Vitamin E, heart disease and false logic...?
Date: 15 Mar 2005 20:03:33 -0800
Message-ID: <>

Here's the abstract of the study, which is called HOPE-TOO (HOPE-The
Ongoing Outcomes = HOPE-TOO . It's an ongoing bit of the HOPE trial
(Heart Outcomes Prevention Evaluation). This is the biggest, longest
prospective blinded and placebo-controlled prospective trial of d-alpha
tocopherol acetate. Basically, vitamin E per se as the d-alpha
tocopherol has been found to do nothing particularly good in heart
disease or diabetes. Worse than that, it increases chance of congestive
heart failure (albeit of a probably mild type). My comments are

"Effects of Long-term Vitamin E Supplementation on Cardiovascular
Events and Cancer: A Randomized Controlled Trial" The HOPE and HOPE-TOO
Trial Investigators* JAMA, Vol. 293, pp. 1338-47 (March 15, 2005).


Context: Experimental and epidemiological data suggest that Vitamin E
supplementation may prevent cancer and cardiovascular events. Clinical
trials have generally failed to confirm benefits, possibly due to their
relatively short duration.

Objective: To evaluate whether long-term supplementation with Vitamin E
decreases the risk of cancer, cancer death, and major cardiovascular

Design, Setting, and Patients:  A randomized, double-blind,
placebo-controlled international trial (the initial Heart Outcomes
Prevention Evaluation [HOPE] trial conducted between December 21, 1993
and April 15, 1999) of patients at least 55 years old with vascular
disease or diabetes mellitus was extended (HOPE-The Ongoing Outcomes
[HOPE-TOO]) between April 16, 1999 and May 26, 2003.

Of the initial 267 HOPE centers that had enrolled 9,541 patients, 174
centers participated in the HOPE-TOO trial. Of 7,030 patients enrolled
at these centers, 916 were deceased at the beginning of the extension,
1,382 refused participation, 3,994 continued to take the study
intervention, and 738 agreed to passive follow-up. Median duration of
follow-up was 7.0 years.

Intervention:  Daily dose of natural source Vitamin E (400 IU) [d-alpha
tocopherol acetate] or matching placebo.

Main Outcome Measures:  Primary outcomes included cancer incidence,
cancer deaths, and major cardiovascular events (myocardial infarction,
stroke, and cardiovascular death). Secondary outcomes included heart
failure, unstable angina, and revascularizations.

Results:  Among all HOPE patients, there were no significant
differences in the primary analysis: for cancer incidence, there were
552 patients (11.6%) in the Vitamin E group vs 586 (12.3%) in the
placebo group (relative risk [RR], 0.94; 95% confidence interval [CI],
0.84-1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%),
respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24); and for major
cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR,
1.04; 95% CI, 0.96-1.14; P = .34). Patients in the Vitamin E group had
a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = .03)
and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P =
..045). Similarly, among patients enrolled at the centers participating
in the HOPE-TOO trial, there were no differences in cancer incidence,
cancer deaths, and major cardiovascular events, but higher rates of
heart failure and hospitalizations for heart failure.

Conclusion:  In patients with vascular disease or Diabetes Mellitus,
long-term Vitamin E supplementation does not prevent cancer nor major
cardiovascular events and may increase the risk for heart failure.


COMMENT by S. Harris:

In the initial shorter duration version of the HOPE trial 3 years ago
(>1800 patients per group), congestive heart failure (CHF) came closest
of any endpoint to being greater in the d-alpha tocopherol acetate 400
IU group, with the RR 1.21 and confidence limits 1.0 - 1.46) p = 0.05.
Hospitalization for CHF didn't come close to significance at p = 0.51.
With larger numbers and longer followup, both these are now significant
in the HOPE-TOO.

The interesting thing is that CHF is usually a consequence of coronary
disease and old MIs. But the number of MIs and other coronary events
really didn't come close to being significantly altered by the vitamin
E in the full study above (which is the only one I have access to,
right now).  The closest of anything was stroke, which had a p of 0.2.
None of the cardiac stuff was much different from RR =1, so it does NOT
look like it was there, but just isn't showing above the noise due to
power problems.

So what's going on?  Of course I have no idea. But this kind of
"congestive heart failure" is not as bad as it sounds to the layman, if
if doesn't increase deaths and doesn't result from any detectable
increase in coronary events. It basically means retention of fluid in
feet or lungs, and hospitalization means there's enough retention in
the lungs to cause problems. We have no way to know if in this study,
the extra cases were due to some global weakening of cardiac function,
or just some odd changes in salt handling and retention (which would of
course be less worrisome). We do know from this and many other studies
that blood pressure and renal function (at least, of the gross
filtration sort) are not affected at all by doses of vitamin E in this
range. So it's a mystery. Still, I'm not going to pretend even this
non-MI-related CHF is okay, although in many practices it would simply
mean an adjustment of diuretic. The bottom line is the only thing
vitamin E does for cardiac patients we can really be sure of, is
something (somewhat) bad.

The main value of these studies is to show that vitamin E as the
d-alpha form, in doses large enough to raise blood levels by 70%, has
NO effect on heart disease progression. Or on diabetes progression. Not
even a hint of it, in a placebo controlled study of many thousands of
people extending many years. I have a whole book (by Wilfred Shute,
M.D. with Harald Taub: _Vitamin E for Ailing and Healthy Hearts_ 1969,
with the 11th paperback printing I have from 1977) claiming that this
very d-alpha tocopherol in similar amounts, is a veritable cure-all for
all cardiac ailments. These claims by the Shute brothers go all the way
back to the 1940's. Every chapter of every health book since the Shutes
started blowing this horn, has had an enormous amount of junk
repetition of all these claims.

Well, these Shute claims appear to be wishful thinking. The real shame
is that it's taken the "medical establishment" half a century to prove
it. And no, there's still no good prospective evidence that vitamin E
prevents cancer in humans, either. (Frankly, I'm a little more hopeful
that selenium will prove out, there. And possibly even vitamin C.)
Vitamin E per se in reasonable and traditional supplemental amounts
(which 400 IU is) certainly doesn't affect onset of diabetes, or
progression of diabetic renal disease. We know that from the HOPE trial
also. I would have wagered a modest amount of money that this wouldn't
be so, from what I know of oxidative mechanisms in diabetes. But I'd
have been wrong. That's why we do these studies.

And no, the HOPE trial goes beyond showing that vitamin E just doesn't
heal the diseased-of-heart (though the Shutes claimed just that). Most
of the HOPE enrollees were not clinically ill, though they did have
coronary disease. If vitamin E even slowed progression of those with
disease, it would have been seen here. It wasn't. The idea that vitamin
E prevents ONSET of coronary disease in totally healthy people who
don't have any at all (if such adults exist in our society), *even
though* it doesn't at all effect progression of disease in people who
already have some, is very far fetched. I think it's grasping at
straws, in fact. I don't believe it, and can't imagine why anybody

Here's the full text of the first phase of the HOPE trial, for the
vitamin E side (as you know, there was another side looking at
preventive effects of giving the ACE inhibitor ramepril).


From: Steve Harris <>
Subject: Re: Vitamin E, heart disease and false logic...?
Date: 16 Mar 2005 12:26:35 -0800
Message-ID: <>

Look, if this study had been done with dl-alpha, critics would be
complaining it wasn't done with the ddd natural isomer. And since it
was done with the d,d,d, now they're complaining it wasn't done with
the proper "natural mix" of alpha, beta, gamma, and delta isomers
(whatever *that* is-- since it varies widely within different foods and
cultural food mixes, and the body can, and does, methylate the more
common natural gamma to more-needed and protein carrier specific

And if the study *had* been done with a 4 isomer mix, the critics would
be complaining that the negative result and the health problems were
due to the fact that it wasn't done with the 4 isomer mix with
chocolate sauce and a blueberry on top. It never ends. If *that* had
been the protocol, the critics would pooh pooh it for omitting a
sprinkling of sesame seeds, rice tocotrienols, and a partridge in a
pear tree.

Look, you health-gurus. Call your shots BEFOREHAND. Don't spend decades
playing up people like the Shutes, and then when they are proven
totally wrong, claim you never heard of them, and certainly didn't
support their views. Sheesh.


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