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.


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 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.


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.


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.


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.


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.



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


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


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?


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.





 Dr. Hank Liers, PhD biography about us HPDI integratedhealth formulator founder CEO scientist physicist curcuminoidsUltimate Protector contains curcuminoids (greater than 95% from turmeric), as well as components from 29 different fruits, vegetables, and herbs. Each of these ingredients contain substances that may be considered to be polyphenols, antioxidants, and Nrf2 activators. In this article I will explore the ingredient curcuminoids, which is added as a separate ingredient.

Curcuminoids are the major active component of turmeric, a yellow compound isolated from the plant Curcuma longa (a member of the ginger family) and has been used for centuries in traditional medicines. Curcuminoids in turmeric include curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin (these are standardized in the Sabinsa Curcumin C3 Complex® ingredient).

turmeric plant curcuminoids

The turmeric plant produces beautiful flowers

Extensive research over the past 30 years indicates that these molecules can provide positive benefits against a wide range of health issues related to cell function, lungs, liver, nervous system, joint function, metabolism, and cardiovascular system. Numerous lines of evidence indicate that curcuminoids are highly pleiotropic with anti-inflammatory, hypoglycemic, antioxidant, wound healing, and antimicrobial activities.

Curcuminoids exert both direct and indirect antioxidant effects by scavenging reactive oxygen species (ROS) and inducing the expression of cytoprotective proteins in an Nrf2-dependent way. It is considered a bifunctional antioxidant. The nuclear-factor-erythroid-2-related factor 2 (Nrf2), is a ubiquitous master transcription factor which induces the endogenous production of cytoprotective proteins/enzymes through binding to antioxidant response elements (AREs) at the DNA/gene level.

An excellent and extensive online source of information on curcuminoids (curcumin) can be found at: http://examine.com/supplements/Curcumin/

Scientific Studies on the Health Protective Effects of Curcuminoids

Databases (like the PubMed database of the National Institutes of Health (NIH)) of scientific studies contain thousands of up-to-date studies and abstracts about curcumin/curcuminoids.

Curcumin curcuminoids

Turmeric root is the source of curcuminoids

Below we provide a few relevant scientific studies on the antioxidant effects and potential health benefits of curcumin/curcuminoids.


Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets


Curcumin (diferuloylmethane), a yellow pigment in the spice turmeric (also called curry powder), has been used for centuries as a treatment for inflammatory diseases. Extensive research within the past two decades has shown that curcumin mediates its anti-inflammatory effects through the downregulation of inflammatory transcription factors (such as nuclear factor kappaB), enzymes (such as cyclooxygenase 2 and 5 lipoxygenase) and cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6). Because of the crucial role of inflammation in most chronic diseases, the potential of curcumin has been examined in neoplastic, neurological, cardiovascular, pulmonary and metabolic diseases. The pharmacodynamics and pharmacokinetics of curcumin have been examined in animals and in humans. Various pharmacological aspects of curcumin in vitro and in vivo are discussed in detail here.


Antioxidant and anti-inflammatory properties of curcumin


Curcumin, a yellow pigment from Curcuma longa, is a major component of turmeric and is commonly used as a spice and food-coloring agent. It is also used as a cosmetic and in some medical preparations. The desirable preventive or putative therapeutic properties of curcumin have also been considered to be associated with its antioxidant and anti-inflammatory properties. Because free-radical-mediated peroxidation of membrane lipids and oxidative damage of DNA and proteins are believed to be associated with a variety of chronic pathological complications such as cancer, atherosclerosis, and neurodegenerative diseases, curcumin is thought to play a vital role against these pathological conditions. The anti-inflammatory effect of curcumin is most likely mediated through its ability to inhibit cyclooxygenase-2 (COX-2), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS). COX-2, LOX, and iNOS are important enzymes that mediate inflammatory processes. Improper upregulation of COX-2 and/or iNOS has been associated with the pathophysiology of certain types of human cancer as well as inflammatory disorders. Because inflammation is closely linked to tumor promotion, curcumin with its potent anti-inflammatory property is anticipated to exert chemopreventive effects on carcinogenesis. Hence, the past few decades have witnessed intense research devoted to the antioxidant and anti-inflammatory properties of curcumin. In this review, we describe both antioxidant and anti-inflammatory properties of curcumin, the mode of action of curcumin, and its therapeutic usage against different pathological conditions.


Curcumin: The Indian Solid Gold


Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 Bc) numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer’s disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than monotargeted therapy for most diseases, curcumin can be considered an ideal “Spice for Life”.


Curcumin decreases oxidative stress in mitochondria isolated from liver and kidneys of high-fat diet-induced obese mice


Oxidative stress plays a key role in obesity and diabetes-related mitochondrial dysfunction. Mitochondrial dysfunction is characterized by increased oxidative damage, nitric oxide (NO) synthesis, and a reduced ratio of adenosine-5′-triphosphate (ATP) production/oxygen consumption. Curcumin represents a potential antioxidant and anti-inflammatory agent. In this study, our objective was to determine the effect of curcumin treatment on oxidative stress and mitochondrial dysfunction in high-fat diet (HFD)-induced obese mice (OM). These results suggest that curcumin treatment increased oxygen consumption and significantly decreased lipid and protein oxidation levels in liver mitochondria isolated from HFD-induced OM compared with those in the untreated OM (UOM). In kidney mitochondria, curcumin treatment significantly increased oxygen consumption and decreased lipid and protein peroxidation levels in HFD-induced OM when compared with those in UOM. Curcumin treatment neither has any effect on body weight gain nor have any effects on mitochondrial NO synthesis. These findings suggest that obesity induces oxidative stress and mitochondrial dysfunction, whereas curcumin may have a protective role against obesity-induced oxidative stress and mitochondrial dysfunction.


Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients.

From: http://www.ncbi.nlm.nih.gov/pubmed/23745991


Radiation dermatitis occurs in approximately 95% of patients receiving radiotherapy (RT) for breast cancer. We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the ability of curcumin to reduce radiation dermatitis severity in 30 breast cancer patients. Eligible patients were adult females with noninflammatory breast cancer or carcinoma in situ prescribed RT without concurrent chemotherapy. Randomized patients took 2.0 grams of curcumin or placebo orally three times per day (i.e., 6.0 grams daily) throughout their course of RT. Weekly assessments included Radiation Dermatitis Severity (RDS) score, presence of moist desquamation, redness measurement, McGill Pain Questionnaire-Short Form and Symptom Inventory questionnaire. The 30 evaluable patients were primarily white (90%) and had a mean age of 58.1 years. Standard pooled variances t test showed that curcumin reduced RDS at end of treatment compared to placebo (mean RDS = 2.6 vs. 3.4; P = 0.008). Fisher’s exact test revealed that fewer curcumin-treated patients had moist desquamation (28.6% vs. 87.5%; P = 0.002). No significant differences were observed between arms for demographics, compliance, radiation skin dose, redness, pain or symptoms. In conclusion, oral curcumin, 6.0 g daily during radiotherapy, reduced the severity of radiation dermatitis in breast cancer patients.


Curcumin attenuates insulin resistance in hepatocytes by inducing Nrf2 nuclear translocation

From: http://europepmc.org/abstract/med/22024084


BACKGROUND/AIMS: NF-E2-Related Factor-2 (Nrf2) is a transcription factor that plays a crucial role in the cellular protection against oxidative stress. Curcumin has been reported to induce Nrf2 nuclear translocation and upregulate the expression of numerous reactive oxygen species (ROS) detoxifying and antioxidant genes in hepatocytes.This study was designed to investigate whether curcumin-induced Nrf2 nuclear translocation could reduce ROS-mediated insulin resistance in cultured LO2 hepatocytes. METHODOLOGY: Human LO2 hepatocytes were incubated with curcumin and glucose oxidase (GO) in the presence/absence of wortmannin (a phosphatidyinositol 3-kinase (PI3K) inhibitor). Oxidative stress, cellular damage, Nrf2 nuclear translocation and insulin resistance were measured. RESULTS: GO exposure significantly increased intracellular ROS, glutathione (GSH) depletion, malondialdehyde (MDA) formation, and increased activities of cellular lactate dehydrogenase (LDH) and aspartate amino transferase (AST), as well as causing insulin resistance. Curcumin pretreatment significantly attenuated these disturbances in intracellular ROS, liver enzyme activity and significantly antagonized the lipid peroxidation, GSH depletion and insulin resistance induced by GO in LO2 hepatocytes. These effects paralleled Nrf2 nuclear translocation induced by curcumin. Wortmannin partially blocked curcumin-induced Nrf2 nuclear translocation. In addition, wortmannin prevented curcumin-induced improvements in intracellular ROS, MDA formation, GSH depletion, liver enzyme activity and insulin resistance in cultured LO2 hepatocytes. CONCLUSIONS: These findings suggest that curcumin could reduce ROS-mediated insulin resistance in hepatocytes, at least in part through nuclear translocation of Nrf2.


Long Term Effect of Curcumin in Restoration of Tumour Suppressor p53 and Phase-II Antioxidant Enzymes via Activation of Nrf2 Signalling and Modulation of Inflammation in Prevention of Cancer

From: http://www.greenmedinfo.com/article/curcumin-potentiated-significant-increase-nrf2-activation-it-restored-activityPLoS One.


Inhibition of carcinogenesis may be a consequence of attenuation of oxidative stress via activation of antioxidant defence system, restoration and stabilization of tumour suppressor proteins along with modulation of inflammatory mediators. Previously we have delineated a significant role of curcumin during its long-term effect in regulation of glycolytic pathway and angiogenesis, which in turn results in prevention of cancer via modulation of stress activated genes. The present study was designed to investigate long-term effects of curcumin in regulation of Nrf2 mediated phase-II antioxidant enzymes, tumour suppressor p53 and inflammation under oxidative tumour microenvironment in liver of T-cell lymphoma bearing mice. Inhibition of Nrf2 signalling observed during lymphoma progression, resulted in down regulation of phase II antioxidant enzymes, p53 as well as activation of inflammatory signals. Curcumin potentiated a significant increase in Nrf2 activation. It restored activity of phase-II antioxidant enzymes like GST, GR, NQO1, and tumour suppressor p53 level. In addition, curcumin modulated inflammation via upregulation of TGF-β and reciprocal regulation of iNOS and COX2. The study suggests that during long term effect, curcumin leads to prevention of cancer by inducing phase-II antioxidant enzymes via activation of Nrf2 signalling, restoration of tumour suppressor p53 and modulation of inflammatory mediators like iNOS and COX2 in liver of lymphoma bearing mice.


Curcumin Activates the Heme Oxygenase-1 Gene via Regulation of Nrf2 and the Antioxidant Responsive Element

From: http://www.academia.edu/309816/Curcumin_Activates_the_Haem_Oxygenase-1_Gene_via_Regulation_of_Nrf2_and_the_Antioxidant-Responsive_Element


The transcription factor Nrf2, which normally exists in an inactive state as a consequenceof binding to a cytoskeleton-associated protein Keap1, can be activated by redox-dependent stimuli. Alteration of the Nrf2/Keap1 interaction enables Nrf2 to translocate to the nucleus, bind to the antioxidant responsive element (ARE) and initiates the transcription of genes encoding for detoxifying enzymes and cytoprotective proteins. This response is also triggered by a class of electrophilic compounds including polyphenols and plant-derived constituents. Recently, the natural antioxidants curcumin and caffeic acid phenethyl ester (CAPE) have been identified as potent inducers of heme oxygenase-1 (HO-1), a redox-sensitive inducible protein that provides protection against various forms of stress. Here, we show that in renal epithelial cells both curcumin and CAPE stimulate the expression of Nrf2 in a concentration- and time-dependent manner. This effect was associated with a significant increase in HO-1 protein expression and hemeoxygenase activity. From several lines of investigation we also report that curcumin (and, by inference, CAPE) stimulates HO-1 gene activity by promoting inactivation of the Nrf2/Keap1 complex leading to increased Nrf2 binding to the resident HO-1 AREs. Moreover, using antibodies and specific inhibitors of the mitogen-activated protein kinase (MAPK) pathways, we provide data implicating p38 MAPK in curcumin-mediated HO-1 induction. Taken together, these results demonstrate that induction of HO-1 by curcumin and CAPE requires the activation of the Nrf2/ARE pathway.


Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.


The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.



Curcuminoids are important polyphenols, antioxidants, and Nrf2 activators that help make Ultimate Protector an outstanding nutritional supplement.