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PRO-C ANTIOXIDANT FORMULA UPDATE + VIDEO

Dr. Hank Liers, PhD pro-c™ pro-c super antioxidant formulaFred Liers PhD pro-c antioxidant vitamin c nrf2 formulaLooking for an advanced antioxidant formula? Already using or recommending vitamin C? Curious about cellular Nrf2 activation? Look no further than PRO-C™.

PRO-C™ is among the most effective antioxidant formulas available. It is an HPDI foundational supplement that works most effectively when used with multivitamins, essential fats, and superfoods. However, it is also an excellent standalone formula that can rapidly provide the body with extremely high protection from free radicals.

We ourselves have taken PRO-C daily for many years with excellent results. Our personal experience together with detailed feedback from health professionals and end-users affirms the effectiveness of PRO-C as a super-antioxidant–vitamin C-Nrf2 activator formula.

PRO-C provides 500 mg of buffered vitamin C per capsule (buffered with calcium, magnesium, and zinc) along with grape extract (seed, skin, pulp) and green tea extract (95% polyphenols). In addition, we include a special combination of the “network antioxidants” l-glutathione (reduced), n-acetyl-l-cysteine (NAC), r-lipoic acid, and selenium. Vitamin B2 and Vitamin B6 in coenzyme forms support the enzymatic effectiveness of the “network antioxidants”. The formula works so well because this combination of ingredients leverages the antioxidant power of vitamin C, grape extract, green tea extract, and the other nutrients to act synergistically in order to maximize effectiveness.

FORMULATION HISTORY AND THE SCIENCE BEHIND PRO-C™

What you may not know is the history of the development PRO-C and the scientific knowledge on which Dr. Hank Liers based his formulation of it.

Dr. Hank formulated his first product in 1989. It was a potent antioxidant formula he called PYC-C™ (sounds like “pixie”). PYC-C consisted of a combination of buffered Vitamin C (including magnesium, calcium, and zinc ascorbates) and pycnogenols from pine bark.

Much of the scientific research data Dr. Hank collected during the development of PYC-C regarding oligomeric proanthocyanidins (OPC) he later incorporated into an article (currently published on this blog) titled “Review of Scientific Research on Oligomeric Proanthocyanidins (OPC)” (rev. 2017)

By 1997 Dr. Hank had gathered a great deal of new scientific information regarding green tea catechins and the nutrients termed “network antioxidants” by Dr. Lester Packer, director of Packer Lab at University of California, Berkeley. Beyond this information, Dr. Hank studied additional research regarding how various nutrients worked together synergistically. At that point, he was ready to formulate the new, improved PRO-C™ super antioxidant formula.

PRO-C combines the ingredients of PYC-C (now known as OPC-C™) and uses grape pulp, skin, and seed extract with green tea extract (with high polyphenols >95% and EpiGalloCatechinGalate (EGCG) >45%), n-acetyl-l-cysteine (NAC), reduced glutathione (GSH), R-lipoic acid, selenium, and coenzyme Vitamins B2 and B6.

PRO-C super antioxidant formula 180 cap 90 cap

HPDI launched PRO-C™ in late 1997. It rapidly became one of our best-selling products. Our customers raved about how effective it was for them if they felt like they were “coming down with something” (like a cold, flu, virus, infection, etc.). Greater skin elasticity greatly helped pregnant women avoid stretch marks and episiotomies. Today, we highly recommend its use together with our other Foundational Supplements to ensure optimal health and anti-aging effects.

THE PRO-C™ SUPER ANTIOXIDANT FORMULA

PRO-C™ super antioxidant formula is extremely synergistic, especially in so far as it increases the body’s ability to quench free radicals in its aqueous (i.e., water-based) compartments. Because antioxidants may become free radicals themselves after they have done their job, the body has developed an elaborate system for recovery of oxidized antioxidants.

 

Dr. Lester Packer was the primary researcher investigating the synergistic character of antioxidants. He made this statement in his interview with Dr. Richard Passwater after publication of Packer’s The Antioxidant Miracle (1999):

[The major theme of] The Antioxidant Miracle is that antioxidants work in a coordinated manner. They interact with one another, and this interaction, which we like to call the antioxidant network, is very important to the overall antioxidant defense that we possess. The key members of the antioxidant network are vitamin E and vitamin C, but there are other participants in this network. These are thiol antioxidants, antioxidants that contain sulfur groups in the body. Glutathione perhaps is the best known of these, but there are other sulfur-containing antioxidants that also are very important.”

Dr. Packer continues:

“This whole antioxidant network works like an orchestra depending on individuals who have, of course, different complements of antioxidants depending upon their nutritional regimens and the individuality of their own body metabolisms. The idea behind having a network of antioxidants is that if one antioxidant happens to be deficient the others can compensate and still keep the antioxidant defense system strong.”

The following diagram shows some of the relationships in the antioxidant network and how they support each other.

Lester Packer antioxidant network diagram Figure 1 – Dr. Packer’s Antioxidant Network

We see, for example, reduced glutathione (GSH) has the ability to reduce oxidized Vitamin C back to its unoxidized state. Vitamin C reduces oxidized Vitamin E back to its unoxidized state, and both reduces glutathione and spares it for other important functions, including detoxification and immune enhancement.

Many polyphenols (e.g., oligomeric proanthocyanidins (OPCs), anthocyanidins and catechins) found in red grape and green tea extracts spare Vitamin C and glutathione in the body, as well as operate as powerful antioxidants, anti-inflammatories, and connective tissue strengtheners.

grapes grape extract antioxidant

Grapes provide antioxidant nutrients such as polyphenols, OPCs, anthocyans, and resveratrol.

R-Lipoic Acid (see abstracts below) operates as an antioxidant both in its oxidized and reduced states, reduces the oxidized forms of both Vitamin E and Vitamin C, and and has been shown to enhance glutathione levels. Because several of these substances are able to protect Vitamin E contained in cell membranes, this combination also has a significant beneficial effect on the fat soluble antioxidant status of the body!

The nutrients in PRO-C have been carefully selected and balanced to provide optimal effects, especially as related to free radical protection, detoxification, immune system enhancement, connective tissue strengthening, and reduction of inflammation. PRO-C therefore provides outstanding nutritional support in a wide variety of conditions of poor health, as well as acts to support and maintain a state of health and well-being.

It the last several years the research results on Nrf2 activators have become well known and products developed that take advantage of these nutrients. For details see our blog article Natural Phytochemical Nrf2 Activators for Chemoprevention. Researchers have been studying specifically how enzyme-activating substances such as OPCs and anthocyans activate a transcription factor known as Nrf2 that causes the body to endogenously produce higher levels of a wide variety of protective enzymes including superoxide dismutase (SOD), catalase, and glutathione peroxidase.

Although we did not know about Nrf2 activators in 1997 when we formulated PRO-C, we have subsequently learned that four of the ingredients in the formula have powerful Nrf2 activity. These include grape seed extract, green tea extract, NAC, and r-lipoic acid. With this knowledge, we now understand that PRO-C provides both powerful external antioxidants (with extremely high ORAC5.0 values) that support redox cycles within the body, but also provides ingredients that allow the body to endogenously produce powerful protective enzymes for even greater free-radical protection and health.

PRO-C™ ANTIOXIDANT FORMULA INGREDIENTS

PRO-C contains buffered vitamin C (in the form of powdered calcium, magnesium, and zinc ascorbates), high-potency grape extract (from grape pulp, skins, and seeds), green tea extract (with>95% polyphenols and >45% EGCG), reduced glutathione, N-Acetyl-L-Cysteine (NAC), R-lipoic acid, coenzyme forms of vitamin B2 (R5P) and vitamin B6 (P5P), and selenium.

Below we will discuss each ingredient and show some of the research that confirms its effectiveness.

VITAMIN C

Vitamin C typically is called l-ascorbic acid or ascorbate and is an essential nutrient for humans and other animal species. The term “vitamin C” refers to a number of vitamins that have vitamin C activity in animals, including ascorbic acid and its salts (e.g., magnesium ascorbate, calcium ascorbate, sodium ascorbate, etc.), and some oxidized forms such as dehydroascorbate and semidehydroascorbate.

Vitamin C is known to perform many critical functions within the body involving detoxification, tissue building, immune enhancement, pain control, and controlling or killing pathogenic organisms. It is also known to be helpful for wound and bone healing, healthy skin and eyes, fighting infections, stress control, toxic exposure, and repairing damaged tissue of all types. For much more information on the many benefits of Vitamin C see our blog article Vitamin C – An Amazing Nutrient.

Below are two abstracts that show some of the beneficial effects of Vitamin C when used with other network antioxidants:

ABSTRACT 1:
Exhaustive physical exercise causes oxidation of glutathione status in blood: prevention by antioxidant administration.
Sastre J, Asensi M, Gasco E, Pallardo FV, Ferrero JA, Furukawa T, Vina J
In: Am J Physiol (1992 Nov) 263(5 Pt 2):R992-5

We have studied the effect of exhaustive concentric physical exercise on glutathione redox status and the possible relationship between blood glutathione oxidation and blood lactate and pyruvate levels. Levels of oxidized glutathione (GSSG) in blood increase after exhaustive concentric physical exercise in trained humans. GSSG levels were 72% higher immediately after exercise than at rest. They returned to normal values 1 h after exercise. Blood reduced glutathione (GSH) levels did not change significantly after the exercise. We have found a linear relationship between GSSG-to-GSH and lactate-to-pyruvate ratios in human blood before, during, and after exhaustive exercise. In rats, physical exercise also caused an increase in blood GSSG levels that were 200% higher after physical exercise than at rest. GSH levels did not change significantly. Thus, both in rats and humans, exhaustive physical exercise causes a change in glutathione redox status in blood. We have also found that antioxidant administration, i.e., oral vitamin C, N-acetyl-L- cysteine, or glutathione, is effective in preventing oxidation of the blood glutathione pool after physical exercise in rats.

ABSTRACT 2:
The effect of glutathione and vitamins A, C, and E on acute skin flap survival.

Hayden RE, Paniello RC, Yeung CS, Bello SL, Dawson SM
In: Laryngoscope (1987 Oct) 97(10):1176-9

Vitamins A, C, and E act as antioxidants and as free radical scavengers in biological systems. Glutathione is involved in several reactions in vitamin metabolism and also plays an important role in cell membrane protection against lipid peroxidation by free radicals. We sought to use these natural defense mechanisms against oxygen free radicals formed during reperfusion of ischemic skin flaps. An acute axial random skin flap model was utilized in the rat. Vitamins or glutathione were administered by oral gastric tube or intravenously in the perioperative period, and survival of the flap was measured at 1 week. Glutathione, beta-carotene, ascorbic acid and alpha-D- tocopherol showed mean flap survival of 84% to 89%, each of which was significantly improved over saline controls (67% p less than .0005). The mechanisms and biochemistry of these vitamins, and their interactions with other vitamins and with glutathione, are discussed, along with clinical implications of free radical scavenging and skin flap survival.

GRAPE EXTRACT

Grape extract (seeds, skin, pulp) contain highly bioavailable bioflavonoid complexes that in research studies have been shown to have powerful antioxidant capability. The Oligomeric Proanthocyanidins (OPCs) in grape seed extract are able to strengthen collagen fibers in aging or damaged connective tissue and can act as a preventative against connective tissue degradation.

Some research indicates that anthocyans, which are found in extracts of grape skin and stems (but not in grape seed extract), can reduce oxidized glutathione while at the same time become reduced themselves. In addition, extracts of grape skin and stems (but not those of grape seed extract) contain a material called trans-resveratrol that has been shown to have chemopreventive effects.

Below we have provided some of the abstracts that are included in our broad list of relevant abstracts for PRO-C.

ABSTRACT 3:
Protective effects of grape seed proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid peroxidation and DNA fragmentation, and peritoneal macrophage activation in mice.
Bagchi D, Garg A, Krohn RL, Bagchi M, Bagchi DJ, Balmoori J, Stohs SJ
In: Gen Pharmacol (1998 May) 30(5):771-6

1. The comparative protective abilities of a grape seed proanthocyanidin extract (GSPE) (25-100 mg/kg), vitamin C (100 mg/kg), vitamin E succinate (VES) (100 mg/kg) and beta-carotene (50 mg/kg) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced lipid peroxidation and DNA fragmentation in the hepatic and brain tissues, as well as production of reactive oxygen species by peritoneal macrophages, were assessed. 2. Treatment of mice with GSPE (100 mg/kg), vitamin C, VES and beta-carotene decreased TPA-induced production of reactive oxygen species, as evidenced by decreases in the chemiluminescence response in peritoneal macrophages by approximately 70%, 18%, 47% and 16%, respectively, and cytochrome c reduction by approximately 65%, 15%, 37% and 19%, respectively, compared with controls. 3. GSPE, vitamin C, VES and beta-carotene decreased TPA-induced DNA fragmentation by approximately 47%, 10%, 30% and 11%, respectively, in the hepatic tissues, and 50%, 14%, 31% and 11%, respectively, in the brain tissues, at the doses that were used. Similar results were observed with respect to lipid peroxidation in hepatic mitochondria and microsomes and in brain homogenates. 4. GSPE exhibited a dose-dependent inhibition of TPA- induced lipid peroxidation and DNA fragmentation in liver and brain, as well as a dose-dependent inhibition of TPA-induced reactive oxygen species production in peritoneal macrophages. 5. GSPE and other antioxidants provided significant protection against TPA-induced oxidative damage, with GSPE providing better protection than did other antioxidants at the doses that were employed.

ABSTRACT 4:
Clinical and capillaroscopic evaluation of chronic uncomplicated venous insufficiency with procyanidins extracted from vitis vinifera
Costantini A, De Bernardi T, Gotti A
In: Minerva Cardioangiol (1999 Jan-Feb) 47(1-2):39-46

BACKGROUND: The pharmacological treatment of non-complicated chronic venous insufficiency is a current and well-debated topic. The introduction of new products with action on the venous system, improved knowledge on the physiopathology of venous insufficiency and the possibility provided by new analytical instruments, have given new impulse to the consolidation of the clinical value of phlebotonics in this indication. METHODS: In light of this, 24 patients with non-complicated chronic venous insufficiency were treated with oral administration of Oligomeric Proanthocyanidins (Pycnogenols-OPC) 100 mg/day. To evaluate the therapeutic efficacy of the treatment, an instrumental evaluation by optical probe capillaroscope was employed in addition to the traditional subjective clinical parameters: swelling, itching, heaviness and pain. The videocapillaroscope examination was performed at the lower third of the leg and the first toe. Edema in the capillaroscopic field, the number of observable capillaries and the capillary dilatation were the parameter chosen to evaluate the efficacy of treatment. All patients completed the study with no reports of adverse events during the period of observation. RESULTS: The results obtained show a positive clinical response (improved or absent symptoms) in over 80% of patients, with significant improvement of symptoms already evident after the first 10 days of treatment. The mechanism of action of the OPCs explains the rapid reduction of the swelling of the lower limbs and correlated with this are the other evaluable symptoms: heaviness and itching. Particularly striking results were observed for itching and pain which completely disappeared during the course of therapy in 80% and 53% of the patients respectively. Noteworthy is the good correlation between the clinical and instrumental data, with improvement in a total of 70% of patients. CONCLUSIONS: The results obtained in the course of this clinical experience, with evident improvement already during the first weeks of treatment, the absence of adverse events added to the benefit of a once-a-day administration, justify the use of OPC in the treatment of non-complicated chronic venous insufficiency.

ABSTRACT 5:
Polymeric procyanidin fraction from defatted grape seeds protects HepG2 cells against oxidative stress by inducing phase II enzymes via Nrf2 activation.
Younghwa Kim, Youngmin Choi, Hyeonmi Ham, Heon-Sang Jeong, Junsoo Lee
Kim, Y., Choi, Y., Ham, H. et al. Food Sci Biotechnol (2013) 22: 485. https://doi.org/10.1007/s10068-013-0105-x

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that regulates antioxidant response element (ARE)-driven phase II detoxification enzymes. In this study, induction of phase II enzymes via Nrf2/ARE activation in the cytoprotective effect of crude polyphenol extract (CPE), oligomeric procyanidin fraction (OPF), and polymeric procyanidin fraction (PPF) from defatted grape seeds in HepG2 cells was evaluated. Among these treatments, the treatment with PPF significantly increased Nrf2 protein expression in the nuclear fraction. Treating the samples increased heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) protein expression in a dose-dependent manner, and PPF significantly increased the levels of phase II enzymes. Cellular generation of reactive oxygen species (ROS) were effectively reduced by PPF. These results suggest that pretreatment with PPF shows a cytoprotective effect by inhibiting ROS production and inducing HO-1 and NQO1 expression via Nrf2 activation in HepG2 cells.

GREEN TEA EXTRACT

Green tea extract is obtained from the unfermented leaves of Camellia sinensis for which numerous biological activities have been reported including: antimutagenic, antibacterial, hypocholesterolemic, antioxidant, and protective against tumorigenesis. Below we have selected a few of the many abstracts we have on file showing the benefit of green tea extract.

Green tea antioxidant polyphenols catechins

Green tea leaves are high in antioxidant polyphenols and catechins.

ABSTRACT 6:
Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in drinking water to SKH-1 hairless mice: possible role in cancer chemoprevention.
Khan SG, Katiyar SK, Agarwal R, Mukhtar H
In: Cancer Res (1992 Jul 15) 52(14):4050-2

Following the oral feeding of a polyphenolic fraction isolated from green tea (GTP) in drinking water, an increase in the activities of antioxidant and phase II enzymes in skin, small bowel, liver, and lung of female SKH-1 hairless mice was observed. GTP feeding (0.2%, w/v) to mice for 30 days significantly increased the activities of glutathione peroxidase, catalase, and quinone reductase in small bowel, liver, and lungs, and glutathione S-transferase in small bowel and liver. GTP feeding to mice also resulted in considerable enhancement of glutathione reductase activity in liver. In general, the increase in antioxidant and phase II enzyme activities was more pronounced in lung and small bowel as compared to liver and skin. The significance of these results can be implicated in relation to the cancer chemopreventive effects of GTP against the induction of tumors in various target organs.

ABSTRACT 7:
INHIBITORY EFFECT OF SIX GREEN TEA CATECHINS AND CAFFEINE ON THE GROWTH OF FOUR SELECTED HUMAN TUMOR CELL LINES.
In: Anticancer Drugs (1996 Jun) 7(4):461-8
Institutional address: Department of Pharmacology and Toxicology College of Pharmacy University of Arizona Tucson 85721 USA.

Green tea is an aqueous infusion of dried unfermented leaves of Camellia sinensis (family Theaceae) from which numerous biological activities have been reported including antimutagenic, antibacterial, hypocholesterolemic, antioxidant, antitumor and cancer preventive activities. From the aqueous-alcoholic extract of green tea leaves, six compounds (+)-gallocatechin (GC), (-)-epicatechin (EC), (-)- epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)- epigallocatechin gallate (EGCG) and caffeine, were isolated and purified. Together with (+)-catechin, these compounds were tested against each of four human tumor cells lines (MCF-7 breast carcinoma, HT-29 colon carcinoma, A-427 lung carcinoma and UACC-375 melanoma). The three most potent green tea components against all four tumor cell lines were EGCG, GC and EGC. EGCG was the most potent of the seven green tea components against three out of the four cell lines (i.e. MCF-7 breast cancer, HT-29 colon cancer and UACC-375 melanoma). On the basis of these extensive in vitro studies, it would be of considerable interest to evaluate all three of these components in comparative preclinical in vivo animal tumor model systems before final decisions are made concerning which of these potential chemopreventive drugs should be taken into broad clinical trials.

GLUTATHIONE AND N-ACETYL-L-CYSTEINE (NAC)

Glutathione and NAC (a major precursor of glutathione) both provide important protection against toxins and free radicals, and can strengthen the immune system. Glutathione is considered to be one of the most important protective substances in the human body with almost 60% of liver detoxification accounted for by this key substance. In addition, glutathione is one of the most potent anti-viral substances known.

Some research has indicated that glutathione may not be able to enter easily into certain types of cells, but NAC is able to enter these cells and be converted into glutathione once inside the cell. Thus, the combination of glutathione and NAC appear to be more potent than either alone.

Below we provide some of the key abstracts we have on file regarding NAC and glutathione.

ABSTRACT 8
GSH rescue by N-acetylcysteine.
Ruffmann R Wendel A
In: Klin Wochenschr (1991 Nov 15) 69(18):857-62

Reduced glutathione (GSH) is the main intracellular low molecular weight thiol. GSH acts as a nucleophilic scavenger and as an enzyme-catalyzed antioxidant in the event of electrophilic/oxidative tissue injury. Therefore, GSH has a major role as a protector of biological structures and functions. GSH depletion has been recognized as a hazardous condition during paracetamol intoxication. Conversely, GSH rescue, meaning recovery of the protective potential of GSH by early administration of N-acetylcysteine (NAC), has been found to be life-saving. Lack of GSH and electrophilic/oxidative injury have been identified among the causes of the adult respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and the acquired immunodeficiency syndrome (AIDS). Experimental and early clinical data (in ARDS) point to the role of NAC in the treatment of these conditions. Recently, orally given NAC has been shown to enhance the levels of GSH in the liver, in plasma, and notably in the bronchoalveolar lavage fluid. Rescue of GSH through NAC needs to be appreciated as an independent treatment modality for an array of different disease, all of which have one feature in common: pathogenetically relevant loss of GSH.

ABSTRACT 9
Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine.
Bridgeman MM Marsden M MacNee W Flenley DC Ryle AP
In: Thorax (1991 Jan) 46(1):39-42

N-acetylcysteine (600 mg/day) was given to patients by mouth for five days before bronchoscopy and bronchoalveolar lavage to determine whether N-acetylcysteine could increase the concentrations of the antioxidant reduced glutathione in plasma and bronchoalveolar lavage fluid. Bronchoalveolar lavage was performed 1-3 hours (group 2, n = 9) and 16-20 hours (group 3, n = 10) after the last dose of N-acetylcysteine and the values were compared with those in a control group receiving no N-acetylcysteine (group 1, n = 8). N-Acetylcysteine was not detected in plasma or lavage fluid. Plasma concentrations of cysteine, the main metabolite of N-acetylcysteine and a precursor of reduced glutathione, were greater in the groups receiving treatment (groups 2 and 3) than in group 1. Cysteine concentrations in lavage fluid were similar in the three groups. Concentrations of reduced glutathione were greater in both plasma and lavage fluid in group 2 than in group 1. These data suggest that N-acetylcysteine given by mouth is rapidly deacetylated to cysteine, with resulting increases in the concentrations of cysteine in plasma and of reduced glutathione in plasma and the airways, which thus temporarily increase the antioxidant capacity of the lung.

R-LIPOIC ACID / ALPHA-LIPOIC ACID

R-Lipoic Acid is normally made at low levels in the human body, where it functions primarily as an important metabolic nutrient in the conversion of pyruvic acid into acetyl coenzyme A. As such, it plays a crucial role in the metabolism of both fats and carbohydrates into energy. In addition, r-lipoic acid functions as an extremely powerful antioxidant capable of trapping many different types of free radicals in the body.

Because it is both water and fat soluble, lipoic acid is able to operate in a broader range of body tissues than most other antioxidants. Its small size allows lipoic acid to enter areas of the body not easily accessible to many other substances; this allows lipoic acid, for example, to enter the cell nucleus and prevent free-radical damage to DNA.

Because it is such a powerful antioxidant and can easily function as such in both a reduced and oxidized state, lipoic acid is able to protect other important antioxidants such as glutathione, Vitamin E, and Vitamin C. R-lipoic acid is also able to chelate heavy metals such as lead, cadmium, mercury, free iron, and free copper out of the body.

Below we provide relevant scientific abstracts from our database regarding R-Lipoic acid.

ABSTRACT 10:
Alpha-Lipoic acid as a biological antioxidant.
Packer L Witt EH Tritschler HJ
In: Free Radic Biol Med (1995 Aug) 19(2):227-50

alpha-Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of iron. alpha-Lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia-reperfusion injury, diabetes (both alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review the properties of lipoate in terms of (1) reactions with reactive oxygen species; (2) interactions with other antioxidants; (3) beneficial effects in oxidative stress models or clinical conditions.

ABSTRACT 11:
Regeneration of glutathione by α-lipoic acid via Nrf2/ARE signaling pathway alleviates cadmium-induced HepG2 cell toxicity.
Zhang J, Zhou X, Wu W, Wang J, Xie H, Wu Z.
In: Environ Toxicol Pharmacol. 2017 Apr;51:30-37. doi: 10.1016/j.etap.2017.02.022. Epub 2017 Feb 27.

Alpha-lipoic acid (α-LA) is an important antioxidant that is capable of regenerating other antioxidants, such as glutathione (GSH). However, the underlying molecular mechanism by which α-LA regenerates GSH remains poorly understood. The current study aimed to investigate whether α-LA regenerates GSH by activation of Nrf2 to alleviate cadmium-induced cytotoxicity in HepG2 cells. In the present study, we found that cadmium induced cell death by depletion of GSH through inactivation of Nrf2. Addition of α-LA to cadmium-treated cells reactivated Nrf2 and regenerated GSH through elevating the Nrf2-downstream genes γ-glutamate-cysteine ligase (γ-GCL) and GR, both of which are key enzymes for GSH synthesis. However, blocking Nrf2 with brusatol in the cells co-treated with α-LA and cadmium reduced the mRNA and the protein levels of γ-GCL and GR, thus suppressed GSH regeneration by α-LA. Our results indicated that α-LA activated Nrf2 signaling pathway, which upregulated the transcription of the enzymes for GSH synthesis and therefore GSH contents to alleviate cadmium-induced cytotoxicity in HepG2 cells.

SELENIUM

Selenium has been shown by clinical research to be a key mineral in the body’s defenses against free radicals and has been shown to be a major factor in reducing the symptoms of HIV infections and in the prevention of tumors. Selenium is used in conjunction with glutathione to form the powerful enzyme glutathione peroxidase that is responsible for detoxification of peroxides formed during the process of aerobic metabolism in humans and other animals.

ABSTRACT 12
Serum selenium concentrations in rheumatoid arthritis.
In: Ann Rheum Dis (1991 Jun) 50(6):376-8

O’Dell JR, Lemley-Gillespie S, Palmer WR, Weaver AL, Moore GF, Klassen LW

Selenium is a trace element and an essential part of the enzyme glutathione peroxidase, which protects cells from oxidative damage. Selenium has been shown to have antiproliferative, anti-inflammatory, antiviral, and immune altering effects. Serum selenium concentrations in 101 patients with seropositive rheumatoid arthritis were found to be significantly lower than those in 29 normal, healthy controls (mean (SD) 148 (42) v 160 (25) micrograms/l) and also lower than those in eight patients with fibrositis (148 (42) v 166 (25) micrograms/l). It is speculated that serum selenium concentrations may modulate the effect of viral or other infections in subjects with the appropriate genetic background and in this way enhance the development or progression of rheumatoid arthritis.

ABSTRACT 13
Studies on selenium in top athletes.
Dragan I, Ploesteanu E, Cristea E, Mohora M, Dinu V, Troescu VS
In: Physiologie (1988 Oct-Dec) 25(4):187-90

The authors performed a controlled trial in 18 top athletes (9 weight lifters and 9 rowers, girls) in order to make evident some chronic and acute effects (antioxidant) of selenium. Nonprotein–SH (essential glutathione), lipid peroxides (MDA-malondialdehyde), glucose-6-phosphate dehydrogenases (G-6-PDH) and fructose-1,6- diphosphate aldolase in serum, have been recorded initially on basal conditions, after 3 weeks of treatment (100 micrograms/day selenium or placebo) and again after 3 weeks of treatment, also on basal conditions, when crossing over the groups (between a free interval of 10 days). In another trial we registered these parameters on basal conditions and after two hours of hard training accompanied by a per oral administration of 150 micrograms selenium (respectively placebo). The results show significant changes under selenium treatment of the peroxides, G-6-PDH and light changes, not significant of the nonprotein–SH, changes which could suggest an antioxidant effect of this element.

VITAMINS B2 and B6 IN COENZYME FORMS

Vitamin B2 as coenzyme riboflavin-5-phosphate is a key vitamin that supports the regeneration of glutathione (via glutathione reductase). Vitamin B6 as coenzyme pyridoxal-5-phosphate is a key vitamin that supports the ability of glutathione to combine with toxic substances (via glutathione transferase) in the process of eliminating them from the body. They are especially effective in their coenzyme forms which allows them to be directly utilized by the body starting in the intestinal tract.

MAGNESIUM, CALCIUM, AND ZINC

Magnesium, zinc, and calcium synergistically work with (and enhance the effects of) the other ingredients in PRO-C. Minerals are especially needed as active components of enzymes that drive metabolic activity. For example, magnesium is required in the functioning of more than 325 types of enzymes.

PRO-C™ SUPER ANTIOXIDANT FORMULA BENEFITS

HIGHLY EFFECTIVE VITAMIN C FORMULA PLUS ANTIOXIDANTS. A complete vitamin C formula, a powerful antioxidant Formula, and Nrf2 activator combined in a single advanced supplement!

POWERFUL, SYNERGISTIC FREE-RADICAL QUENCHING FORMULA. PRO-C™ components work together to quench free radicals in your body. Vitamin C enables grape seed extract to function more effectively, and conversely grape seed extract potentiates vitamin C. Green tea extract boosts ORAC (Oxygen Radical Absorbance Capacity) value.

PROVIDES SIGNIFICANT AMOUNTS OF POWERFUL NRF2 ACTIVATORS (from Grape Extract, Green Tea Extract, NAC, and R-Lipoic Acid) that stimulate the production of the body’s own protective antioxidants including superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase.

SUPERIOR, BUFFERED (NON-ACIDIC) FORM OF VITAMIN C. Mineral Ascorbates never acidify your body, keeping you pH balanced. Staying alkaline is an important element in maintaining a healthy body.

RAPID ASSIMILATION. Capsule form ensures rapid uptake and assimilation in the body. You may also empty capsule contents into water, food, or directly Into mouth, if desired. Good, mildly tart taste!

COMPOSITION OF PRO-C™ SUPER ANTIOXIDANT FORMULA

One (1) vegetarian capsule of PRO-C provides the following percentages of the Daily Value:

NUTRIENT AMOUNT % Daily Value
Vitamin C (from mineral ascorbates) 500 mg 833%
BioVin® Grape Extract 30 mg *
Green Tea Extract 30 mg *
Calcium (from calcium ascorbate) 23 mg 2.3%
Magnesium (from magnesium ascorbate) 23 mg 5.7%
L-Glutathione (reduced) 20 mg *
N-Acetyl-L-Cysteine (NAC) 15 mg *
R-Lipoic Acid 5 mg *
Zinc (from zinc ascorbate) 2 mg 13%
Vitamin B2 (from riboflavin-5′-phosphate) 1 mg 118%
Vitamin B6 (from pyridoxal-5′-phosphate) 1 mg 50%
Selenium (from l-selenomethionine) 10 mcg *

* No established Daily Value

DIRECTIONS: As a dietary supplement take 1–3 capsules or more daily in divided doses (i.e., spread out over the day), or as recommended by a health care professional. It initially may be useful to take up to 6 capsules per day in divided doses for one week. The contents of the capsule may be emptied into juice or food, as needed.

INGREDIENTS: PRO-C™ SUPER ANTIOXIDANT FORMULA contains only the highest-quality USP grade magnesium ascorbate, USP grade calcium ascorbate, BioVin® grape extract (greater than 75% polyphenols, 55% OPC, greater than 3.5% anthocyanidins from grape pulp, skins, and seeds, and a small amount of trans resveratrol), green tea extract (95% min. polyphenols and 45% min. EGCG), l-glutathione (reduced), USP grade n-acetyl-l-cysteine, USP grade zinc ascorbate, r-(+)-lipoic acid, riboflavin-5′-phosphate, pyridoxal-5′-phosphate, l-selenomethionine, the smallest amounts of microcrystalline cellulose and silica in a vegetarian capsule.

PRO-C™ does not contain wheat, rye, oats, corn antigen, barley, gluten, soy, egg, dairy, yeast, sugar, sulfates, phosphates (other than coenzyme forms), fats, chlorides, GMOs, wax, preservatives, colorings, or artificial flavorings.

Click here to order PRO-C™.

SOURCES & RESOURCES

BOOKS

The Antioxidant Miracle. Lester Packer, PhD, and Carol Coleman. New York: John Wiley and Sons, 1999.

How to Live Longer and Feel Better. Dr. Linus Pauling. Corvallis, OR: Oregon State University Press, 2006.

ARTICLES

Review of Scientific Research on Oligomeric Proanthocyanidins (OPC)” (rev. 2017) by Hank Liers, PhD

“Vitamin C – An Amazing Nutrient” by Hank Liers, PhD

PRO-C™ and Ultimate Protector™ – Comparison by Hank Liers, PhD

“Antioxidant Cocktail Update: Part 1: The Take Home Message is to Use Antioxidant Supplements”
(An interview of Dr. Lester Packer by Richard A. Passwater, PhD, Whole Foods Magazine 1999)

ABSTRACTS

PRO-C™ / Vitamin C Abstracts

Catechin Abstracts

N-Acetyl-L-Cysteine (NAC) Abstracts

Lipoic Acid Abstracts

WEBSITES

Orthomolecular.org
(Therapeutic Nutrition Based Upon Biochemical Individuality)

PRODUCTS

PRO-C™Super Antioxidant Formula

Ultimate Protector™Nrf2 Activator Formula

OPC-C™

HPDI Vitamin C Products

HOMOCYSTEINE GENETICS – COENZYME B VITAMINS

Dr. Hank Liers, PhD homocysteine coenzyme B vitaminsWe previously published an article titled FOLATE INGREDIENTS – FOLINIC ACID & 5-MTHF in which we discuss how coenzyme folate vitamins are far superior to the synthetic folic acid form. In today’s article, I take a more in-depth look at how homocysteine is formed from methionine, how genetics affects the metabolic pathways, and how B vitamins are used in metabolic pathways.

One way to look at the metabolic pathways of methionine (an essential amino acid) is that it provides a way for the body to convert this sulfur containing amino acid either to cysteine and its key by-products glutathione, taurine, and sulfates or allows remethylation back to methionine to occur using either the Folate Cycle or the Trimethyl glycine (betaine) pathways.

Figure 1 shows these metabolic pathways including the vitamins required at each step including vitamin B6 (as P-5-P), methylcobalamin, and 5-methyltetrahydrofolate (5-MTHF). In addition, it shows the key enzymes produced by the body at each step. These enzymes include CBS (cystathione beta synthase), BHMT (betaine homocysteine methyltransferase), MS (methionine synthase), and MTHFR (methylene tetrahydrofolate reductase).

homocysteine metabolism diagram

Figure 1. Metabolic Pathways in Methionine and Homocysteine Metabolism

HEALTH ISSUES ASSOCIATED WITH HIGH HOMOCYSTEINE LEVELS

It is highly important that the various metabolic pathways function correctly to keep homocysteine at healthy levels (6–8 µmol/L). Unfortunately, high levels of homocysteine in the body (10–20 µmol/L) are a factor in a wide range of health issues, including:

  • Greater risk for heart problems, including coronary artery disease, heart attacks, stroke, high blood pressure, congestive heart failure, and abnormal cholesterol levels. This is due to increased inflammation, sometimes due to blood clotting spontaneously, and because of blockages of the major arteries.
  • Mental abnormalities such as depression, anxiety, bipolar disorder, and other mental problems are more common among people with high homocysteine
  • Migraines and headaches in a significant percentage of the population
  • In those who suffer from high homocysteine due to having nutritional deficiencies anemia, aches and pains, hearing loss, age-related macular degeneration (ARMD), slowed development, and birth defects might also be possible
  • Greater risk for dementia, Alzheimer’s disease, brain atrophy, and other cognitive problems
  • In children, skeletal and developmental abnormalities including having a curved spine or protruding chest and rib cage. Some patients appear very tall and thin, and some might also have very long, thin “spider-like” toes and fingers.
  • Behavioral problems, including ADHD, autism and other learning disabilities

ROLE OF GENETICS IN HOMOCYSTEINE METABOLISM

Ten or more years ago, questions of how genetics enters into homocysteine metabolism were unlikely to be asked. However, in recent years DNA testing has advanced and is now available to everyone (for example, see my article about Bodysync’s genetic test, DISCOVERING NUTRITIONAL NEEDS THROUGH ADVANCED GENETIC TESTING.

You may have heard a great deal about MTHFR (methylene tetrahydrofolate reductase). This gene is involved in folate metabolism and has a central role in methylation processes like repair of and building new DNA in dividing cells.

In the remethylation pathway for conversion of homocysteine to methionine, MTHFR plays a key role in converting folate into 5-MTHF which is needed along with B12 as methylcobalamin in order for the conversion to take place. Genetic variations in MTHFR have been studied in depth. Of the many variations studies the most significant ones appear to be variations of C677C such as C677T (referred to as heterozygous) or T677T (referred to as homozygous). The heterozygous variant appears in about 30–50% of the population and causes somewhat less efficiency in the conversion of folic acid to 5-MTHF. However, the homozygous variation occurs in about 10% of the population and can have serious effects due to converting little homocysteine back to methionine.

Another variation in MTHFR is called A1298A. These variations are A1298C and C1298C and will have similar effects to the C677C variations. It was interesting to me when I recently analyzed my Bodysync genetic test results showing I carry the variation A1298C (heterozygous), which indicates I may not be effectively converting homocysteine back to methionine.

Additionally, my Bodysync genetic test results also indicate that I have heterozygous variations in the CBS enzyme shown in Figure 1, as well as heterozygous variations in MTR and MTRR enzymes, which are involved with B12 levels in the remethylation pathway. These results indicate that I need to take higher levels of methylcobalamin and 5-MTHF.

IMPORTANCE OF COENZYME FORMS AND PROPER AMOUNTS OF B VITAMINS

Many of the B vitamins on the market today unfortunately are in synthetic form. The body can only use the natural coenzyme forms effectively. For example, the body needs vitamin B6 in the form of P-5-P (pyridoxal-5-phosphate), folate in the form of L-5-MTHF, and B12 in the form of methylcobalamin for proper metabolism of methionine. In some cases the body can use the synthetic forms of pyridoxine HCl, folic acid, and cyanocobalamin but pays a cost (e.g., in time and energy) by having to convert synthetic forms to coenzyme forms.

Add to the prevalence of synthetic B vitamins, the fact that genetic deficiencies are more common than previously assumed, and it becomes clear that the coenzyme forms of B vitamins in the proper amounts are extremely important.

Fortunately, I have always believed it best to include as many coenzyme forms as possible in the nutritional supplements I formulate (over the past 27 years). For example, all HPDI multivitamins include coenzymes of B1, B2, B6, B12, and folate (as 5-MTHF and folinic acid). This is uncommon in most multivitamin formulas on the market. For this reason our supplements are ideally suited to the prevention or resolution of most genetic problems regarding homocysteine.

In addition, I have always chosen to include higher amounts than most multivitamins on the market. We also make available 5-MTHF one milligram (1 mg) capsules and methylcobalamin five milligram (5 mg) sublingual tablets. When genetic variations are in play as discussed above, then providing relatively higher amounts of coenzyme B vitamins that support important requirements in the body seems necessary.

Interestingly, several other nutrients are involved in the pathways involving methionine and homocysteine. These include zinc, magnesium, and Vitamin B2. Our multivitamin formulas and magnesium formulas, especially Myo-Mag with its coenzyme B1, B2, and B6, are recommended to support these nutrient needs. Finally, it has been found that N-Acetyl-L-Cysteine (NAC) can significantly lower homocysteine (by up to 50%), most likely because its gives the body an excellent source of cysteine without have to use methionine.

SUMMARY

In this article, I have shown the value of the use of genetic testing and high-quality coenzyme B vitamins in resolving health issues associated with high values of homocysteine in the body.

 

SOURCES & RESOURCES

DISCOVERING NUTRITIONAL NEEDS THROUGH ADVANCED GENETIC TESTING.

FOLATE INGREDIENTS – FOLINIC ACID & 5-MTHF

The Homocysteine Revolution by Kilmer S. McCully, MD

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease
(Cell Death and Differentiation 11, S56–S64)

PRODUCTS

5-MTHF
(coenzyme folate)

Methylcobalamin
(vitamin B12)

B-Complex-50

HPDI Multivitamins

2

FOLATE INGREDIENTS – FOLINIC ACID & 5-MTHF

Dr. Hank Liers, PhD 5-MTHF and Folinic Acid folate coenzymeFred Liers PhD 5-MTHF and Folinic Acid folate coenzyme

It is important to know that our scientific knowledge of the B vitamin folate has undergone significant changes in the last 10 years based upon some amazing research studies.

We have come to understand that the biologically active and naturally ocurring folate forms of L-5-methyltetrahydofolate (5-MTHF) and 5-formyltetrahydrofolate (folinic acid) are significantly more effective than folic acid, which is a synthetic oxidized form of folate.

For many years (at least since the 1940s), the only form of folate used in supplements and fortified foods was folic acid. However, a significant body of research has shown that supplemental folic acid may actually accelerate cognitive decline in some older individuals. Folic acid also is being linked to increased risk of colon and rectal cancers, increased risk of childhood asthma born to folic-acid supplemented mothers, and accelerated growth of pre-existing tumors.

Many studies have indicated that a large portion of the population (about 50%) have genetic deficiencies in the enzymes (such as MTHFR) that do not allow the body to properly metabolize folic acid into coenzyme forms needed for proper body function.

Unfortunately, journalists and even many medical professionals haven’t understood that folic acid is not the same as the naturally occurring vitamin folate. Even today, much of the medical mainstream use the terms “folic acid” and “folate” interchangeably. Yet, folic acid is not the same as folate!

The good news is that the folate coenzymes of 5-MTHF and Folinic Acid are now readily available for use in nutritional supplements and are being incorporated into products by knowledgeable companies.

WHAT IS FOLATE?

Folate is a water-soluble B vitamin that is naturally present in foods. Folates are  commonly consumed through a diet of green leafy vegetables, sprouts, fruits, brewer’s yeast, animal products such as milk and dairy products, egg yolk, and liver. Formerly known as “folacin,” folate is the generic term for both naturally occurring food folate and folic acid.

spinach folate

Spinach and other green leafy vegetables provide naturally occurring folate.

When consumed, food folates are often hydrolyzed to the monoglutamate form in the gut prior to absorption by active transport across the intestinal mucosa. Passive diffusion also occurs when pharmacological doses of folic acid are consumed.

Before entering the bloodstream, the monoglutamate form is reduced to tetrahydrofolate (THF) and converted to either methyl or formyl forms. However, both of the metabolically active (coenzyme) forms 5-methyl tetrahydrofolate (5-MTHF) and 5-formyl tetrahydrofolate (also known as folinic acid) are found in foods and can enter the cells with no further modification.

Unfortunately folates contained in foods are unstable and susceptible to oxidation; they rapidly lose activity during food processing, manufacturing and storage and have a bioavailability range of 25–50%, depending on the kind of food. Fresh leafy vegetables stored at room temperature may lose up to 70% of their folate activity within three days and a cooking process in water can increase the loss to 95%.

Humans cannot synthesize folate and because of its water soluble nature, the body stores folate to a limited extent. For this reason folate represents a dietary requirement and must be consumed by diet.

FOLATE DEFICIENCY

Folate deficiency represents one of the most common nutritional deficiencies and may occur when dietary intake is inadequate, when an increased need is not matched by an increased intake (particular physiological conditions such as pregnancy, lactation, child growth), when there is altered absorption/excretion (or losses) and when metabolism or drug use interferes with the ability of the body to use folate.

Several conditions can lead to nutritional folate deficiency. These not only include enzyme defects, malabsorption, digestive system pathology, and liver disease, but also conditions with a high rate of cell turnover such as rapid tissue growth (infants, kids and adolescents), and pregnancy and lactation.

In severe cases deficiency can cause many clinical abnormalities, including macrocytic anemia, cardiovascular diseases, birth neural tube defects (NTDs) and carcinogenesis. Folate deficiency is associated with elevated levels of homocysteine, cerebrovascular and neurological diseases, and mood disorders.

MANY BENEFITS OF FOLATE COENZYMES

Folate coenzymes are responsible for the following metabolic functions and benefits:

1) Formation of purines and pyrimidines, which in turn are needed for synthesis of the nucleic acids DNA and RNA. This is especially important during fetal development in the first trimester in preventing birth defects, such as neural tube defects.

2) Formation of heme, the iron-containing protein in hemoglobin

3) Interconversion of the 3-carbon amino acid serine from the 2-carbon amino acid glycine

4) Formation of the amino acids tyrosine from phenylalanine and glutamic acid from histidine

5) Formation of the amino acid methionine from homocysteine (Vitamin B12 as methylcobalamin also is needed for this conversion). Elevated levels of homocysteine have been implicated in a wide range of health disorders including atherosclerosis, osteoporosis, Alzheimer’s disease, and depression. In the reconversion of homocysteine to methionine the body uses the methionine to make the important amino acid s-adenosylmethionine (SAMe) which is known to be helpful in cases of depression.

6) Synthesis of choline from ethanolamine

7) Formation and maturation of red and white blood cells

8) Conversion of nicotinamide to N’-methylnicotinamide

Numerous drugs are known to inhibit the body’s ability to utilize folate, including: 1) aspirin, 2) cholesterol lowering drugs, 3) oral birth control pills, 4) antacids, and 5) methotrexate when used for rheumatoid arthritis. When taking these drugs (and many others) it is recommended that you take at least 800 mcg daily of folate, preferably as 5-MTHF and folinic acid.

When taking folate it is recommended that you take adequate amounts of Vitamin B12 as methylcobalamin.

DISCUSSION OF FOLATE FORMS

The figure (1.1) shown below provides an overview of how the three forms of folate we will be discussing are metabolized in the cell. Basically the diagram shows that there are two major uses of folate in the body 1) Those dealing with methylation reactions and 2) those dealing with nucleotide biosynthesis, e.g., the production of DNA and RNA.

On the bottom left the diagram shows that 5-MTHF can directly enter the cell and be used for methylation reactions such as the conversion of homocysteine into methionine. On the bottom right the diagram shows that 5-formyl tetrahydrofolate (folinic acid) can directly enter the cell and be used for nucleotide biosynthesis after a few enzymatic conversions.

The top of the diagram shows that folic acid can enter the cell, but must go through a series of enzymatic conversions in order to accomplish what 5-MTHF and folinic acid can accomplish. The box in the lower middle of the diagram indicates where the MTHFR enzyme (see the line with the #5) deficiency can block the metabolism of folic acid.

The diagram shows that all of the important reactions can be accomplished by either 5-MTHF or folinic acid as they can be converted to one another by a series of enzymatic reactions. An important study (see abstract below) has indicated that at least in some cases the presence of a MTHFR enzyme deficiency does not impede the conversion of folinic acid into 5-MTHF.

Folate Metabolism 5-MTHF and Folinic Acid

1.1. Diagram of Folate Metabolism from Vitamin Analysis for the Health & Food Sciences by Ronald R. Eitenmiller and W.O. Lander, Jr.

FOLIC ACID: Once isolated and exposed to air natural folates in food becomes unstable and breaks down, and are generally no longer useful in nutrition. But a small amount of natural folate can be transformed by oxidation (a natural process) into folic acid, a much more stable form with a very long shelf life.

While human and animal cells cannot use the folic acid molecule itself in their normal metabolic processes, human cells (principally the liver) can transform folic acid back into many of its metabolically useful folate forms. That is why folic acid—despite not being found in food—can do so much nutritional good. The best-known example is the prevention of birth defects including spina bifida, cleft lip, and cleft palate.

As we age, however, our bodies become increasingly slower at transforming folic acid into usefully metabolized folates. That’s probably the reason scientists are finding that folic acid (not folate) is associated with cognitive decline in the elderly. Some of these studies have shown significantly elevated levels of unmetabolized (and therefore not useful) folic acid building up in the bloodstreams of supplemented older individuals.

In addition to worsening folic acid metabolism with age, there are also a significant number (as high as 45 percent or more in some populations) of survivable human genetic defects of folate metabolism (MTHFR deficiency) which make it more difficult or, in some circumstances, impossible for sufferers to make metabolic use of folic acid.

We believe it is time to make folic acid supplements a part of history, and use only forms of naturally occurring folate when we use supplements. Although my company produces a liquid folic acid supplement that has been especially useful for some pregnant women who are experiencing gum problems, we have been incorporating the coenzyme form Folinic Acid into supplements for over 10 years, and recently introduced the metabolically active form L-5-MTHF.

A small amount of folic acid (100–200 micrograms, the amount found in many multiple vitamins at present) is not likely to be a major problem for most people. However, more taken daily for years just might raise your long-term risk of colorectal cancer, cognitive decline, or other symptoms of elevated levels of homocysteine. If higher amounts are unavoidable (for example, until all prenatal vitamins switch from folic acid to folate), taking additional folate as 5-MTHF and Folinic Acid will very likely offset the folic acid still found in the multiple. In this regard, I have over the last five years eliminated folic acid from all of the multivitamins and B-Complex vitamins that we now make available.

FOLINIC ACID: Also known as 5-formyl tetrahydrofolate, it is one active form in a group of vitamins known as folates. In contrast to folic acid, a synthetic form of folate, folinic acid is one of the forms of folate found naturally in foods. In the body folinic acid may be converted into any of the other active forms of folate.

Compared to folic acid, folinic acid is expensive costing about 100 times more. However, the fact that the body only requires small amounts (less than one mg) means that one can obtain a two month supply of folinic acid for less than $10.

Folinic acid has been available as a supplement for more than 10 years and as such has been the form most used as a replacement for folic acid.

5-MTHF: Also known as L-5-methyl tetrahydrofolate, it has been difficult to obtain until recently. An Italian company has made a patented form available (Quatrefolic®) that is combined with a vegetarian glucosamine. This form is particularly stable and highly bioavailable.

5-MTHF costs about 400 times more than folic acid. However, because the body requires less than one milligram (1 mg) on a daily basis, a person can buy a two-month supply for about $20.

5-MTHF is now readily available on the market, thereby making it possible to purchase at reasonable prices both coenzyme forms of folate.

ANXIETY, MIGRAINE HEADACHE, AND VASCULAR PROBLEMS

As we noted, the importance of natural coenzyme forms of folate is highlighted by the large number of people who cannot convert folic acid to folate usable in the body because they lack the enzymes necessary to make this conversion due to genetics, aging, or faulty metabolism.

For the nearly half of all persons (in some populations) having the functional variation (i.e., mutation) on the MTHFR gene resulting in MTHFR deficiency makes them unable to convert folic acid to a folate form like 5-MTHF that usable by cells. This not only means that their bodies have problems processing B-group vitamins, but also can mean they suffer significant deficiencies (as well as elevated blood folate).

Folate deficiencies can lead to anxiety and panic attacks. Moreover, they can lead to other mood issues, miscarriages, as well as vascular conditions. Recall that elevated levels of homocysteine are associated with folate deficiency.

Another area of interest is research indicating that up to 20% of individuals who carry the MTHFR gene experience migraine headaches.

The effectiveness of natural folates for migraine headaches in persons with MTHFR deficiency is becoming more widely known. Here is a TEDx talk by Prof. Lyn Griffiths from the Griffith Health Institute in Australia showing her work with MTHFR deficiency and migraine (https://www.youtube.com/watch?v=BOgbmF0jYd4). This aspect of her work is highlighted near the end of her talk.

The use of natural folates to help individuals suffering from migraine headache is an area holding great promise.

SUMMARY

Folic acid is not the same as folate. Folic acid can present problems in persons lacking the enzymes necessary to convert it into usable forms. Folic acid can also build up in the body in potentially toxic ways.

Supplementing with naturally occurring coenzyme folates, such as 5-MTHF and folinic acid makes sense given advances in our understanding of how the body utilizes dietary folates.

HPDI incorporates natural folate forms into all of its multivitamins and folate products.

ADDITIONAL RESOURCES

ABSTRACTS

Conversion of 5-formyltetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylenetetrahydrofolate reductase gene.

From: http://www.ncbi.nlm.nih.gov/pubmed/10958818

Abstract

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolic acid (5-CH(3)-H(4) folic acid), the methyl donor for the formation of methionine from homocysteine. A common C677T transition in the MTHFR gene results in a variant with a lower specific activity and a greater sensitivity to heat than the normal enzyme, as measured in vitro. This study was undertaken to determine the capacity of homozygotes for the MTHFR C677T transition to convert 5-formyltetrahydrofolic acid (5-HCO-H(4) folic acid) to 5-CH(3)-H(4) folic acid, a process that requires the action of MTHFR. Six subjects homozygous for the C677T transition (T/T) and 6 subjects with wild-type MTHFR (C/C) were given a 5-mg oral dose of (6R:,S:)-5-HCO-H(4) folic acid. Plasma and urine were analyzed for 5-CH(3)-H(4) folic acid concentrations using affinity/HPLC coupled with fluorescence or UV detection. The mean areas under the curves created by the rise and fall of plasma 5-CH(3)-H(4) folic acid after the oral dose did not differ between the two genotypes, 424.5 +/- 140.3 (T/T) vs. 424.1+/- 202.4 h.nmol/L (C/C). There also was no significant difference in the mean cumulative 7-h urinary excretion of 5-CH(3)-H(4) folic acid between the T/T (2.5 +/- 1.4 micromol) and C/C (1.9 +/- 1.0 micromol) genotypes. Under the conditions employed, the conversion of oral 5-HCO-H(4) folic acid to 5-CH(3)-H(4) folic acid is not impaired in persons with the T/T MTHFR genotype. Possible reasons for these findings are discussed.

 

Folate, folic acid and 5-methyltetrahydrofolate are not the same thing.

From: http://www.ncbi.nlm.nih.gov/pubmed/24494987

Abstract

1. Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism. Mammals cannot synthesize folate and depend on supplementation to maintain normal levels. Low folate status may be caused by low dietary intake, poor absorption of ingested folate and alteration of folate metabolism due to genetic defects or drug interactions. 2. Folate deficiency has been linked with an increased risk of neural tube defects, cardiovascular disease, cancer and cognitive dysfunction. Most countries have established recommended intakes of folate through folic acid supplements or fortified foods. External supplementation of folate may occur as folic acid, folinic acid or 5-methyltetrahydrofolate (5-MTHF). 3. Naturally occurring 5-MTHF has important advantages over synthetic folic acid – it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking haematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation. 4. We review the evidence for the use of 5-MTHF in preventing folate deficiency.

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

 Abstract

Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of >200 μg. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6S)-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs.

 

 

1

Supplementing with Folate Coenzymes 5-MTHF and Folinic Acid

Dr. Hank Liers, PhD 5-MTHF and Folinic Acid folate coenzymeOur knowledge of the B vitamin folate has been undergoing major changes in the last ten years. We have come to the understanding that folic acid, a term often loosely identified as the same as folate, is in fact a synthetic oxidized form of folate.

For many years (at least since the 1940s) the ONLY form of folate used in supplements and fortified foods has been folic acid. However, the good news for health is that the folate coenzymes of 5-MTHF and Folinic Acid are now readily available!

Recently, accumulated research has found that supplemental folic acid may actually accelerate cognitive decline in some older individuals. Folic acid also is being linked to increased risk of colon and rectal cancers, increased risk of childhood asthma born to folic-acid supplemented mothers, and accelerated growth of pre-existing cancers.

Unfortunately, journalists and even many medical professionals still haven’t figured out that folic acid is not the same as the naturally occurring vitamin folate. Even today, much of the medical mainstream, uses folic acid and folate as interchangeable terms. But folic acid is not the same as folate!

WHAT IS FOLATE?

Folate is a water-soluble B vitamin that is naturally present in foods. Folates are  commonly consumed through a diet of green leafy vegetables, sprouts, fruits, brewer’s yeast, and animal products such as milk and dairy products, egg yolk and liver. Formerly known as folacin, folate is the generic term for both naturally occurring food folate and folic acid.

When consumed, food folates are often hydrolyzed to the monoglutamate form in the gut prior to absorption by active transport across the intestinal mucosa. Passive diffusion also occurs when pharmacological doses of folic acid are consumed. Before entering the bloodstream, the monoglutamate form is reduced to tetrahydrofolate (THF) and converted to either methyl or formyl forms. However, both of the metabolically active (coenzyme) forms 5-methyl tetrahydrofolate (5-MTHF) and 5-formyl tetrahydrofolate (also known as folinic acid) are found in foods and can enter the cells with no further modification.

Unfortunately folates contained in foods are unstable and susceptible to oxidation; they rapidly lose activity during food processing, manufacturing and storage and have a bioavailability range of 25–50%, depending on the kind of food. Fresh leafy vegetables stored at room temperature may lose up to 70% of their folate activity within three days and a cooking process in water can increase the loss to 95%.

Humans cannot synthesize folate and because of its water soluble nature, the body stores folate to a limited extent. For this reason folate represents a dietary requirement and must be consumed by diet.

FOLATE DEFICIENCY

Folate deficiency represents one of the most common nutritional deficiencies and may occur when dietary intake is inadequate, when an increased need is not matched by an increased intake (particular physiological conditions such as pregnancy, lactation, child growth), when there is altered absorption/excretion (or losses) and when metabolism or drug use interferes with the ability of the body to use folate.

Several conditions can lead to nutritional folate deficiency such as enzyme defects, malabsorption, digestive system pathology, liver disease but also conditions with a high rate of cell turnover such as rapid tissue growth (infants, kids and adolescents) pregnancy and lactation.

In severe cases deficiency can cause many clinical abnormalities, including macrocytic anemia, cardiovascular diseases, birth neural tube defects (NTDs) and carcinogenesis. Folate deficiency is associated with elevated levels of homocysteine, cerebrovascular and neurological diseases, and mood disorders.

MANY BENEFITS OF FOLATE COENZYMES

Folate coenzymes are responsible for the following important metabolic functions and benefits:

1) Formation of purines and pyrimidines, which in turn are needed for synthesis of the nucleic acids DNA and RNA. This is especially important during fetal development in the first trimester in preventing birth defects, such as neural tube defects.

2) Formation of heme, the iron-containing protein in hemoglobin

3) Interconversion of the 3-carbon amino acid serine from the 2-carbon amino acid glycine

4) Formation of the amino acids tyrosine from phenylalanine and glutamic acid from histidine

5) Formation of the amino acid methionine from homocysteine (Vitamin B12 as methylcobalamin also is needed for this conversion). Elevated levels of homocysteine have been implicated in a wide range of health disorders including atherosclerosis, osteoporosis, Alzheimer’s disease, and depression. In the reconversion of homocysteine to methionine the body uses the methionine to make the important amino acid s-adenosylmethionine (SAMe) which is known to be helpful in cases of depression.

6) Synthesis of choline from ethanolamine

7) Formation and maturation of red and white blood cells

8) Conversion of nicotinamide to N’-methylnicotinamide

Other conditions possibly benefiting from folinic acid supplementation include: AIDS/HIV, celiac disease, cervical displasia, cleft palate, Crohn’s disease, diarrhea, gout, high cholesterol, increased fracture of chromosomes, malabsorption and gastrointestinal inflammation, megaloblastic anemia, restless leg syndrome, postpartum depression, sprue, ulcerative colitis, and vitiligo.

Numerous drugs are known to inhibit the body’s ability to utilize folate, including: 1) aspirin, 2) cholesterol lowering drugs, 3) oral birth control pills, 4) antacids, and 5) methotrexate when used for rheumatoid arthritis. When taking these drugs (and many others) it is recommended that you take at least 800 mcg daily of folate, preferably as 5-MTHF and folinic acid. When taking folate it is recommended that you take adequate amounts of Vitamin B12 as methylcobalamin.

DISCUSSION OF FOLATE FORMS

The figure shown below provides an overview of how the three forms of folate we will be discussing are metabolized in the cell. Basically the diagram shows that there are two major uses of folate in the body 1) Those dealing with methylation reactions and 2) those dealing with nucleotide biosynthesis, e.g., the production of DNA and RNA.

On the bottom left the diagram shows that 5-MTHF can directly enter the cell and be used for methylation reactions such as the conversion of homocysteine into methionine. On the bottom right the diagram shows that 5-formyl tetrahydrofolate (folinic acid) can directly enter the cell and be used for nucleotide biosynthesis after a few enzymatic conversions.

The top of the diagram shows that folic acid can enter the cell, but must go through a series of enzymatic conversions in order to accomplish what 5-MTHF and folinic acid can accomplish. The box in the lower middle of the diagram indicates where the MTHFR enzyme deficiency can block the metabolism of folic acid. The diagram shows that all of the important reactions can be accomplished by either 5-MTHF or folinic acid as they can be converted to one another by a series of enzymatic reactions. An important study (see abstract below) has indicated that the presence of a MTHFR enzyme deficiency does not impede the conversion of folinic acid into 5-MTHF.

FolateMetab 5-MTHF and Folinic Acid

Diagram of Folate Metabolism from the book “Vitamin Analysis for the Health & Food Sciences” by Ronald R. Eitenmiller and W.O. Lander.Jr.

FOLIC ACID: Once isolated and exposed to air natural folates in food becomes unstable and breaks down, and are generally no longer useful in nutrition. But a small amount of natural folate can be transformed by oxidation (a natural process) into folic acid, a much more stable form with a very long shelf life.

While human and animal cells cannot use the folic acid molecule itself in their normal metabolic processes, human cells (principally the liver) can transform folic acid back into many of its metabolically useful folate forms. That’s why folic acid—despite not being found in food—can do so much nutritional good, the best-known example being the prevention of birth defects including spina bifida, cleft lip, and cleft palate.

As we age, however, our bodies become increasingly slower at transforming folic acid into usefully metabolized folates. That’s probably the reason scientists are finding that folic acid (not folate) is associated with cognitive decline in the elderly. Some of these studies have shown significantly elevated levels of unmetabolized (and therefore not useful) folic acid building up in the bloodstreams of supplemented older individuals.

In addition to worsening folic acid metabolism with age, there are also a significant number (as high as 45 percent or more in some populations) of survivable human genetic defects of folate metabolism (MTHFR deficiency) which make it more difficult or, in some circumstances, impossible for sufferers to make metabolic use of folic acid.

So we believe that it is time to make folic acid supplements a part of history, and use only forms of naturally occurring folate when we use supplements. Although my company does produce a liquid folic acid supplement that has been especially useful for pregnant women who are experiencing gum problems, we have been making the coenzyme form Folinic Acid available for over 10 years and recently introduced the metabolically active form L-5-MTHF.

A small amount of folic acid (100–200 micrograms, the amount found in many multiple vitamins at present) is not likely to be a major problem for most people. However, more taken daily for years just might raise your long-term risk of colorectal cancer, cognitive decline, or other symptoms of elevated levels of homocysteine. If higher amounts are unavoidable (for example, until all prenatal vitamins switch from folic acid to folate), taking additional folate as 5-MTHF and Folinic Acid will very likely offset the folic acid still found in the multiple. In this regard, I have over the last five years eliminated folic acid from all of the multivitamins and B-Complex vitamins that we now make available.

FOLINIC ACID: also known as 5-formyl tetrahydrofolate, is one active form in a group of vitamins known as folates. In contrast to folic acid, a synthetic form of folate, folinic acid is one of the forms of folate found naturally in foods. In the body folinic acid may be converted into any of the other active forms of folate.

Compared to folic acid, folinic acid is expensive costing about 100 times more. However, the fact that the body only requires small amounts (less than one mg) means that one can obtain a two month supply of folinic acid for less than $10.

Folinic acid has been available as a supplement for more than 10 years and as such has been the form most used as a replacement for folic acid.

5-MTHF: also known as L-5-methyl tetrahydrofolate has been difficult to obtain until recently. An Italian company has made a patented form available (Quatrefolic®) that is combined with a vegetarian glucosamine. This form is particularly stable and highly bioavailable.

5-MTHF costs about 400 times more than folic acid. However, because the body requires less than one milligram (1 mg) on a daily basis, a person can buy a two-month supply for about $20.

5-MTHF is now readily available on the market, thereby making it possible to purchase at reasonable prices both coenzyme forms of folate. I have taken advantage of this in our Mighty Multi-Vite! multivitamin, which includes both 5-MTHF and folinic acid. 

SUMMARY

Folic acid is not the same as folate. Folic acid presents problems in persons lacking the enzymes necessary to convert it into usable forms. Folic acid can also build up in the body in potentially toxic ways. Supplementing with naturally occurring coenzyme folates, such as 5-MTHF and folinic acid makes sense given advances in our understanding of how the body utilizes dietary folates.

ADDITIONAL RESOURCES

ABSTRACTS

J Nutr. 2000 Sep;130(9):2238-42.

Conversion of 5-formyltetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylenetetrahydrofolate reductase gene.

Source

Vitamin Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston MA 02111, USA.

Abstract

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolic acid (5-CH(3)-H(4) folic acid), the methyl donor for the formation of methionine from homocysteine. A common C677T transition in the MTHFR gene results in a variant with a lower specific activity and a greater sensitivity to heat than the normal enzyme, as measured in vitro. This study was undertaken to determine the capacity of homozygotes for the MTHFR C677T transition to convert 5-formyltetrahydrofolic acid (5-HCO-H(4) folic acid) to 5-CH(3)-H(4) folic acid, a process that requires the action of MTHFR. Six subjects homozygous for the C677T transition (T/T) and 6 subjects with wild-type MTHFR (C/C) were given a 5-mg oral dose of (6R:,S:)-5-HCO-H(4) folic acid. Plasma and urine were analyzed for 5-CH(3)-H(4) folic acid concentrations using affinity/HPLC coupled with fluorescence or UV detection. The mean areas under the curves created by the rise and fall of plasma 5-CH(3)-H(4) folic acid after the oral dose did not differ between the two genotypes, 424.5 +/- 140.3 (T/T) vs. 424.1+/- 202.4 h.nmol/L (C/C). There also was no significant difference in the mean cumulative 7-h urinary excretion of 5-CH(3)-H(4) folic acid between the T/T (2.5 +/- 1.4 micromol) and C/C (1.9 +/- 1.0 micromol) genotypes. Under the conditions employed, the conversion of oral 5-HCO-H(4) folic acid to 5-CH(3)-H(4) folic acid is not impaired in persons with the T/T MTHFR genotype. Possible reasons for these findings are discussed.

PMID:

 10958818

[PubMed – indexed for MEDLINE]