In order to understand the writing that follows, I must try to show this formula.
Please excuse this presentation of the thiamine formula. It was made from the Apache Open Office Drawing file. Its representation is incomplete because it does not show the “double bonds”, but it illustrates that the atoms that bind together to form thiamine are in “two rings”. The 6-sided ring on the left is called a pyrimidine ring and the 5-sided one on the right is called a thiazole ring. The CH2 that joins them is called a methylene bridge. This is the naturally occurring thiamine that we must obtain from our diet. Its deficiency causes the classical disease known as beriberi. It is important to understand the atomic construction of thiamine in the discussion that follows concerning its derivatives.
The Vitamin B Research Committee of Japan, a group of university-based researchers, set out to study beriberi in detail, trying to find the best method of treatment for this disease which had been a scourge in Japan for thousands of years. Without covering the specific details, they found that thiamine was converted to a disulfide derivative by an enzyme found in garlic. Because this occurred in other members of the allium species of plants, they called it allithiamine. Thinking at first that thiamine had lost its biologic activity, when tested in animals the new compound was found to have a greater biologic activity than the original thiamine. It was found that the thiazole ring had been opened, creating a disulfide. They began a research program to synthesize a whole group of thiamine disulfides, two of which are shown below.
Although the arrangement of the atoms is different from the thiamine diagram, the important thing to notice is that the thiazole ring (right side) has been opened, creating a disulfide, including what is known as a prosthetic attachment (the part attached to the disulfide). A disulfide is easily reduced (S-S becomes SH) when the molecule comes into contact with the cell membrane. The result is that the prosthetic group is removed and left outside the cell. The remainder of the molecule passes through the cell membrane into the cell. The thiazole ring closes to provide an intact thiamine molecule in the cell. It is inside the cell where thiamine has its activity and so this is an important method of delivering it to where it is needed. It is this ability to pass through the lipid barrier of the cell membrane that has caused allithiamine to be called fat-soluble. It only refers to this ability, however. It is soluble in water and can be given intravenously.
This “fat solubility” is extremely important because dietary thiamine has to be attached to a genetically determined protein, known as a transporter, to gain entry to cells. There are known to be diseases where the transporter is missing. Affected individuals have thiamine deficiency that does not respond to ordinary thiamine and are usually misdiagnosed. Therefore, a disulfide derivative that does not need the transporter is a method by which thiamine can be introduced to the cell when the transporter is missing. There is no difference between allithiamine and thiamine from a biological activity standpoint. It is this ability to pass the active vitamin through the cell membrane into the cell that provides the advantage.
I performed animal and clinical studies with thiamine tetrahydrofurfuryl (TTFD) for many years and found it to be an extremely valuable therapeutic nutrient. Any disease where energy deficiency is the underlying cause may respond to TTFD, unless permanent damage has accrued. Dr. Marrs and I believe that energy deficiency applies to any naturally occurring disease, even when a gene is at fault. For example, Japanese investigators found that TTFD protected mice from cyanide and carbon tetrachloride poisoning, an effect that was not shown by ordinary thiamine (Fujiwara, M. Absorption, excretion and fatal thiamine and its derivatives in the human body. In Shimazono, N, Katsura, E, eds. Beriberi and Thiamine. (pp 120-121) Tokyo, Igaku Shoin Ltd. 1965). They exposed a segment of dog’s intestine, disconnected it from its nerve supply and found that one of the disulfide derivatives stimulated peristalsis (the wavelike movement of the intestine). It is more than likely that TTFD could be used safely in patients with post operative paralysis of the intestine (paralytic ileus).
The Japanese investigators made many disulfide derivatives, testing them individually for their biologic activity. They found that thiamin propyl disulfide gave the best results, but unfortunately gave both treated animals and human subjects a pervasive body odor of garlic. They went on to create TTFD with a deliberate attempt to remove the garlic odor and the commercial product was named Alinamin F (odorless). This is by far the best of the disulfide derivatives. Besides the trade name of Alinamin, the Japanese product, TTFD is sold as Lipothiamine in the United States.
The Japanese investigators synthesized a whole series of thiamine derivatives where the prosthetic group was attached to the carbon atom (bottom right C on the thiazole ring). They are all so-called open ring derivatives but the prosthetic group has to be separated by an enzyme in the body for the thiazole ring to close. The best known of these is known as Benfotiamine and several papers have been published concerning its benefits in the treatment of neuropathy. It has also been published that it does not cross into the brain, whereas TTFD does and this seems to be the major difference between Benfotiamine and Lipothiamine. Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives. It is predictable that TTFD would be the best choice since it has beneficial effects both inside and outside the brain and it certainly needs to be explored and researched further as a very valuable therapeutic agent.
Thiamine is found in health food stores as thiamine hydrochloride and thiamine mononitrate. These are known as “salts” of thiamine. Like dietary thiamine, they require a protein transporter to get the vitamin into the cell. Their absorption used to be thought to be extremely limited, but megadoses are effective in some situations. The absorption of salts is therefore inferior to that of the thiamine derivatives discussed above. They are all so-called “open ring (thiazole)” forms of thiamine and represent the most useful way of getting big doses of thiamine into the cell. The reader should be aware that when we talk about big doses of a vitamin, it is being used as a drug. Although they can be used for simple vitamin deficiency, their medical use goes far beyond that because they can be effective sometimes when thiamine absorption is genetically compromised.
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