Feeding and activating the methylation metabolism

Methylations are extremely important for the growth and differentiation of every cells, even more for gametes and embryos. These reactions add a carbon unit to key molecules to esure the synthesis, among many others, of DNA and RNA. Moreover, the methylation of DNA and histone proteins delivers information of how the DNA is to be used, which is called “epigenetics“.

The methylation capacity is directly determined by our diet that must contain adequate amounts of the necessary substrates. People carrying certain genetic traits (e.g. MTHFR variants) may need a larger feed of these dietary substances and are exposed to shortages. During gametogenesis and embryogenesis there are phases requiring massive methylation capacity that may unmask subclinical deficits resulting in defective epigenetic marking and subsequent failures.

Impryl contains all the substrates required to feed methylations. Moreover, it supplies these substances in a pre-activated form so to be fully efficient in balancing the metabolism also of those carrying defective variants of metabolic enzymes, in particular:

• Folic acid in its methylated, active form (methylfolate) to compensate for a possible defect of the enzyme MTHFR (Methylene-Tetra-Hydro-Folate-Reductase)
• Vitamin B12 in its methylated, active form  (methylcobalamine) to compensate for a possible defect of the enzyme MTRR (5-methyltetrahydrofolate-homocysteine methyltransferase reductase)
• Betaine (trimethyl glycine) to compensate for a possible defect of the enzyme CHDH (choline-dehydrogenase)
• Cysteine donor (L-cystine) to compensate for a possible defect of the enzyme CBS (cystathionine beta synthetase)

Checking the methylation metabolism:
Blood and/or follicular homocysteine

Methylation reactions use the universal physiologic methyl donor, S-adenosyl- Methionine (SAMe). After donating the methyl group, SAMe generates another substance, homocysteine (Hcy). Hcy is then re-methylated to methionine/SAMe by using the methyl donors from the diet.

Accordingly, if there is a shortage of methylation capacity, there may be also an increase of Hcy in blood, in other body fluids and in tissues. This makes Hcy a reliable reporter of the methylation capacity, although problems may occur also with normal Hcy. Besides being a diagnostic marker, Hcy is itself part of the problem because it behaves as a powerful inhibitor of methylations and as pro-oxidant. Increased Hcy is a well known risk factor for a variety of diseases, starting from male and female infertility. Hcy can be tested in blood (morning, fasting), in urine, and in any other body fluid.

Published evidences confirm Impryl as effective dietary tool to reduce the Hcy level. Impryl resulted in a decrease of blood Hcy in all the treated subjects (100% response rate) both in young PCOS ladies (Schiuma et al. 2020) and in infertile men (Clement et al 2023). In women undergoing assisted reproduction it is also possible to measure Hcy in follicular fluids to predict their quality. In a controlled study the occurrence of a pregnancy was inversely related to follicular HCY concentration and Impryl was able to reduce follicular Hcy as well as to improve the clinical outcomes (Kucuk et al 2023).

Everybody can check the own Hcy level either before taking Impryl or after taking it to control the effects. The test is strongly advised by experts for all men and women suffering from infertility and is offered by every clinical lab.

Feeding and activating the endogenous antioxidant system

Impryl is the benchmark of the antioxidants support. According to the new strategy, instead of using antioxidant substances, that act only on a limited number of sensitive pathways and that may generate negative counter effects, Impryl leverages on the physiologic antioxidant system to achieve a better redox balance within the control of the natural cellular homeostasis. This approach is resulting in metabolic improvements that appeared impossible by using traditional antioxidant molecules. In addition Impryl contains only physiologic substances for a safe use with no fixed limits of duration.

The endogenous (physiologic) antioxidant system is based on a wide variety of molecules capable to bring reducing power into specific reactions. All of them, after working as an antioxidant, remain oxidized and can be re-charged with antioxidant capacity by the universal donor of antioxidant power, wich is glutathione (GSH). This is a small molecule produced by every cell in direct relation to the dietary availability of the same substances feeding methylations (see above) and of cysteines (see right). Our cells activate the generation of GSH only where and when it is needed, which avoids any imbalance. However, methylations (epigenetics) enjoy priority. Thus, GSH release will be massive only if the methylation capacity is fully satisfied.

Impryl generates a massive increase of methylation capacity, which triggers GSH’s pathway, while also providing further substrate (L-cystine) for GSH synthesis. The combined effect of this support is an increase of GSH release, which can be large in those with low starting level (actual need).

Thus, the substances provided by Impryl allow the cells to activate the endogenous antioxidant defenses. The resulting antioxidant effect is comprehensive, i.e. affecting all the thousands metabolic reactions of concern, and known to play a beneficial influence on cell growth and differentiation. These effects occur within the control of the physiologic regulation of cellular homeostasis that can align the activity to the actual need.

Checking the antioxidant system:
Blood and/or erythrocyte GSH

GSH is an abundant and ubiquitous molecule. It occurs in either reduced form, GSH, acting as antioxidant, or oxidized form, GSSG, without antioxidant power. Within cells it is almost entirely in reduced form with a ratio of about 100:1. In blood, due to reactions with pro-oxidants, the ratio falls to 6-8:1, still in favor of the reduced form. Cells produce glutathione in the reduced form (GSH) by de-novo synthesis. The reduced power is carried by the -SH (sulfide) group provided by the amino acid cysteine.

Out of cells, GSH is extremely reactive, which frustrates any attempt for an oral administration as supplement: It would react already within the tablet/capsule and, if not, would be certainly consumed by the gut bacteria. Oral antioxidants also fail to feed GSH synthesis. Opposite, they suppress the endogenous release.

Thus, GSH must be produced endogenously using food substrates, in particular proteins containing the suphurated amino acid cysteine (more of it in vegetable proteins). Cysteine itself is not soluble, it is adsorbed from food in the form of L-cystine, which is formed by 2 cysteines. Once into the cell, and at time of actual need, L-cystine releases cysteine and feeds GSH synthesis. Cells can also produce cysteine enodegenously (from Hcy) by the enzyme Cystathionine Beta-Synthase (CBS). CBS gene can occur in a variety of rare pathologic variants as well as in more common defective, although physiologic, variants. Carriers of these variants may be more dependent on the dietary feed of cysteines to compensate.

This is the reason why L-cystine is included in Impryl: It ensures an integration to the daily balance of cysteines, which may be more relevant in carriers of CBS variants or in those consuming a diet low in vegetable proteins. Thus, methyl donors activate the pathway and L-cystine provides the substrate. Impryl may result in an increase of GSH, which can be larger in those starting with a lower value .

The level of GSH can be measured at many clinical labs, the coost should be checked in advance. Labs can measure GSH either in blood or within erythrocytes (red cells) and usually report the concentration of reduced (GSH), oxidized (GSSG) and total glutathione (the sum of the formers) as well they calculate the ratio of GSH:GSSG. A low GSH and/or a bad GSH to GSSG ratio should be corrected by dietary adjustments.