I have only a few comments by way of amplification/elucidation and
have snipped the rest.

On 02/04/2009 06:33 PM, Ólafur Páll Ólafsson wrote:
> that the function of proteins and enzymes (most enzymes are proteins)
> is highly dependent on their shape and form.

Actually, *all* enzymes are proteins. A scientifically accurate
definition of enzyme (the one referenced by the MoreLife.org glossary)
is at: http://www.mondofacto.com/facts/dictionary?enzyme
Anything that is not a protein may even be a catalyst for exactly the
same reaction, but it is not correctly called an enzyme.

> When a protein becomes
> glycated the first step in the glycation is the attachment of a sugar
> molecule to an amino group on the protein. After the attachment the
> shape and form of the protein has changed. Depending on where the
> glycation occurred on the protein this can have various effects such
> as e.g. reduced function of the protein. The role of lipids in the
> body is different.

Both lipids and carbohydrates are not the active workhorses of all
life-forms that proteins are. Lipids and carbohydrates are generally
used for fuel, as additions to proteins or peptides (smaller chains of
amino acids than proteins, not directly manufactured from DNA
expression) or as structural components (cellulose - carbohydrates, and
cell membranes - lipids). The term "lipid" is also applied to fatty
acids that have an amino acid or peptide appended to them, even
(incorrectly) to proteins that are carriers/transporters of lipids and
even (very incorrectly) to describe cholesterol - which is not
technically a lipid at all, even though being lipophilic (literaly -
lipid loving) cholesterol is always associated with lipids. Therefore,
when you read about glycated lipids, you should realize that it is not
the fatty acid molecule or triglyceride (more technically called a
triacylglyerol and there are many dozens of kinds of them) that is
glycated (that is impossible in the normal meaning of "glycated"), but
rather an amino acid appendage or protein carrier of it.

> There is need for more research in this area but in
> general I do not think glycation of lipids is as harmful as that of
> proteins.

Glycation of the protein lipid carriers (through the blood) and
transporters (across cell membranes) is likely to be important since
that will cause them to be less functional. However, when the correct
definition of lipids is used, Olafur is quite correct here. Lipid
glycation is almost certain to be less important overall than protein
glycation. Still I agree that more research is needed in this area.

>> (http://pubmed.gov/17449494, August 2007:
>> Streptozotocin (STZ)-induced diabetic rats were treated by oral
>> administration of PLP or pyridoxamine (PM), another active form of
>> vitamin B6, at a dose of 600 mg/kg/day for 16 weeks. ... PLP was
>> superior to PM in inhibiting accumulation of AGEs, expression of
>> TGF-beta1, type 1 collagen, and fibronectin, and the development of
>> diabetic nephropathy.
>
> Now this is a study I had not seen before. I am surprised to see that
> PLP was found to be superior to pyridoxamine in that study. Except for
> this study, the only study of which I am aware that directly compares
> PLP to pyridoxamine is this one: http://pmid.us/8602828 . That is an
> in vitro study. In that study pyridoxamine was found to be the most
> effective antiglycating compound followed by PLP, pyridoxal and
> pyridoxine. Why PLP was found to be more effective than pyridoxamine
> in the above study is difficult to say. There are reasons to suspect
> this would not apply to humans.

I concur, and it is only one study contrary to the weight of evidence of
many, many others that show pyridoxamine to be superior, although not
that much so over PL or PLP.

> The absorption of phosphorylated forms of vitamin B6 generally starts
> with hydrolysis by alkaline phosphatase in the digestive tract. PLP
> thus will be hydrolized to pyridoxal before being absorbed. If this is
> the case PLP should not be any more effective than pyridoxal as an
> antiglycative agent when taken orally. However when very high doses
> are taken some of the PLP may escape hydrolysis and be absorbed
> intact.

The latter does not really make any difference, because PLP is
dephosphorylated back to PL as it leaves the intestinal mucosa cells and
enters the capillaries nourishing the intestinal wall cells and thence
into the portal vein into the liver.

> From the full text of http://pmid.us/479949 :
>
> "At physiological doses PLP is absorbed largely after hydrolysis to
> PL, though a small percentage is absorbed without hydrolysis. This
> direct absorption of PLP which is several fold slower than PL could be
> important only at doses well above physiological level."
>
> Normally the majority of PLP will be hydrolized and absorbed as
> pyridoxal but when high doses are taken some of it may be absorbed
> intact. How high is difficult to say though but this may explain the
> results of the above study since in that study a very high dose of PLP
> was used. Most certainly some of it was absorbed intact without first
> being hydrolized allowing PLP to provide beneficial antiglycating
> protection.

Recall that "hydrolyzed" in this case means "dephosphorylated". For
details on this see my comments in:
http://health.groups.yahoo.com/group/morelife/message/1976
"Absorbed" above means only going from the intestines to the portal vein
where all of it ends up as PLP, no matter how it started out or got
there from the intestines.

> But I don't think this means PLP by an oral route is
> superior to pyridoxamine for humans. The dose used in the above study
> amounts to about 12g of PLP for a 70kg human. That is an extremely
> large dose! To put it into perspective vitamin B6 generally causes
> neurotoxicity at doses in excess of 1g per day in humans. There are
> even reports of neurotoxicity from taking vitamin B6 in doses as low
> as 100-300mg http://pmid.us/16320662 . For prevention 400mg per day of
> vitamin B6 is about the most I would recommend to any adult human.
> Thus as is so often the case this study has no applicability to
> chronic human intakes of vitamin B6 for prevention.

For humans, 12 g per day would almost certainly cause peripheral
neuropathy within days to weeks, and for any longer period would likely
cause irreversible brain damage. Overdosing of B6 (particularly
pyridoxine) is not something to play around with!

> Furthermore pyridoxamine has several studies supporting it's efficacy
> against glycation in both humans and animals while PLP has much fewer.
> Newertheless this study does suggest that PLP may be superior to
> pyridoxal as well as the commonly used pyridoxine when it comes to
> antiglycative function particularly when high doses of PLP are taken.

It may "suggest" that, but, based on all other studies, I have little
confidence in that possibility.

>> Finally, in this study, http://pubmed.gov/18004515,
>> Amino acids react with methylglyoxal to form advanced glycation end
>> products. This reaction is known to produce free radicals. In this
>> study, cleavage to plasmid DNA was induced by the glycation of lysine
>> with methylglyoxal in the presence of iron(III). This system was found
>> to produce superoxide as well as hydroxyl radicals. The abilities of
>> various vitamins to prevent damage to plasmid DNA were evaluated.
>> Pyridoxal-5-phosphate showed maximum protection, while pyridoxamine
>> showed no protection. The protective abilities could be directly
>> correlated to inhibition of production of hydroxyl and superoxide
>> radicals. Pyridoxal-5-phosphate exhibited low radical scavenging ability
>> as evaluated by its TEAC, but showed maximum protection probably by
>> interfering in free radical production. Pyridoxamine did not inhibit
>> free radical production.
>>
>
> I am surprised by the results of the above study, particularly these
> parts:
> "The protective abilities could be directly correlated to inhibition
> of production of hydroxyl and superoxide radicals. ... Pyridoxamine
> did not inhibit free radical production."
>
> This is surprising in light of the fact that pyridoxamine has been
> shown to be able to scavenge free radicals, including the hydroxyl
> radical http://pmid.us/18374270 .
>
> This study suggests that under some conditions PLP may be superior to
> pyridoxamine with respect to inhibiting glycation. But keep in mind
> that this is an in vitro study. A large portion of the PLP taken
> orally will generally be hydrolized to pyridoxal before being absorbed.

Also keep in mind that free radical scavenging ability is not a major
benefit of any form of B6. There are many more potent scavengers and
there is even great doubt, particularly in recent years, that the major
benefit of most ingested chemicals is their free radical scavenging
strength. The body's modulating abilities of all its internal free
radical scavengers is very strong and likely to completely dominate
effects from outside. There are several recent review papers
essentially making this point.

--Paul