The human body relies heavily on enzymes to perform all sorts of functions such as: the breakdown of various foods so that the nutrients can be absorbed, accelerating various chemical reactions which otherwise would be too slow for the requirements of the body, and generating energy quickly and efficiently among others. Then there is a whole series of enzymes whose job is to detoxify chemicals, either foreign (toxins) or ones produced by the body itself including hormones like estrogen. One such large group of enzymes is called the cytochrome P450 (CYP) family which breaks down different chemicals and thus reduces the circulating levels in the blood. In 1989, a researcher by the name of Bailey accidently discovered that while masking the taste of alcohol with grapefruit juice, the metabolism or breakdown of a drug he was studying was greatly reduced. Later, it was found that components in grapefruit caused interactions with many other types of drugs; in fact 60% of drug actions are affected by grapefruit juice!
What is the mechanism of this interaction? Various components in grapefruit juice like bergamottin interfere with the proper working of one specific member of the CYP P450 family called CYP3A4, which is responsible for metabolizing a large percentage of drugs. Once the CYP3A4 is inhibited, the drug in question stays in the body for a longer period and may thus cause a potentially serious interaction. Generally, a reduction in the dose of the drug is required to prevent toxicity. Pharmacists will often warn patients about grapefruit juice-drug interactions.
Estrogen is one such hormone that is broken down by CYP3A4 especially in premenopausal women when estrogen production is ripe. This becomes less of an issue for women once they approach menopause since estrogen levels go down dramatically. Estrogen is a hormone that causes cells in various tissues like the breast and the uterus to multiply. Now, if the breakdown of estrogen is prevented because the enzyme that breaks it down is inhibited by grapefruit juice, then it is conceivable the levels of estrogen will rise and the hormone will stay longer in the body causing proliferation of tissues and may lead to breast cancer.
Researchers at the University of Hawaii argued that grapefruit juice or fruit would cause an increase in the risk of breast cancer by inhibiting the CYP3A4 enzyme. They investigated the association between grapefruit juice intake and the risk of breast cancer in five different ethnic groups. After adjusting for age, body weight, life style (e.g. smoking), diet (overall caloric intake) and other factors, the researchers noticed that indeed the levels of estrogen were higher in women that regularly ate or drank grapefruit juice. From a consumption of only a quarter of a grapefruit daily, the researchers estimated it may result in a 30% increased risk of breast cancer!
But what about all the fiber and flavonoids that grapefruit is rich in, aren’t these healthy and beneficial against cancer you say? Indeed that would be the case, yet where is the evidence to counteract the findings of the Hawaiian researchers? Researchers at Harvard University lead by William Willett, a giant in the field of nutrition and health took a closer look at the University of Hawaii study. They found in their very large Nurses’ Health Study population that grapefruit juice or fruit intake did NOT result in increased breast cancer risk; rather it had a protective effect.
The contrasting conclusions in the above studies highlight the major drawback of epidemiological or population based studies including: first, that it is difficult to control for the many confusing factors (confounding) even adjusting for such variations is very difficult; second, most of the data regarding intake is derived from self-assessment questionnaires which unfortunately have a serious flaw and finally, perhaps the most important, people are individuals and thus have unique biological responses to diets and supplements that may be different from another person. This last point is what the late great Dr. Roger Williams argued when he proposed his seminal theory of biochemical variation which suggests the urgent need for personalized nutrition.
Monore, KR et-al “Prospective study of grapefruit intake and risk of breast cancer in postmenopausal women: the Multiethnic Cohort Study” Br J Cancer, 2007; 97:440-445
Kim EH et-al “A prospective study of grapefruit and grapefruit juice intake and breast cancer risk” Br J Cancer, 2008; 98:240-241
Not surprisingly, improving the bioavailability has turned out to be the holy grail in the halls of natural product research labs the world over. There are many ways to improve bioavailability, these can range from: incorporating compounds like curcumin into “cage-like” molecules called cyclodextrins, to combining ingredients with powerful polymers (called block polymers), to forming extremely small-size micro or nano-emulsions, to using powerful surfactants like Tween, or by making the curcumin more lipid-soluble by coating it with various phospholipids usually derived from soy. Unfortunately, many of these methods use unapproved ingredients as per regulatory authorities like Health Canada or the FDA. Still others use ingredients that would not be considered food-grade or natural and are thus considered inappropriate.
Then there is the case where some companies use piperine, an alkaloid from black pepper. Black pepper is a widely consumed spice and has been used for centuries by virtually every culture. The rationale for the use of piperine to enhance the bioavailability of curcumin and other ingredients is that piperine inhibits or “knocks-out” the phase 2 enzyme system whose job is to attach various groups like glucuronide or sulphate to any molecule friend or foe that enters the blood. Phase 2 enzymes are a family of enzymes that literally act as the last line of our defence system. Attaching these groups makes molecules more soluble and thus easily excreted through the urine. For friendly molecules like curcumin, or the various flavonoids like quercetin which we get from fruits and vegetables, that’s not good since they are quickly excreted before much benefit can be derived. However, for unfriendly molecules like carcinogens, solvents (from petrol fumes or paints), chemicals or prescriptive drugs, then phase 2 enzymes are really useful. The longer these molecules stay in the body, the greater harm they can cause. So the phase 2 enzyme system is there for a reason and that is to protect us. No wonder this enzyme system is described as the major detoxification pathway. You don’t want to fiddle with it, especially if inhibiting it.
It is strange indeed that no one seems to have raised this alarming concern about inhibiting the phase 2 enzymes, this “gatekeeper”, while possibly allowing the good guys like curcumin to stay in the body but also allowing the “bad” guys like carcinogens to stay as well! The only person to have ever raised this issue is Clark Sayer. Sayer has been a lone voice for well over five years, and surprisingly when this matter is brought up at scientific discussions researchers generally agree with him. Surely then, isn’t it better not to use this ingredient as a bioavailability enhancer until more research actually proves its usefulness and safety? However, quite a few companies continue to use this approach of inhibiting this key detoxification system! Far better to use other approaches like solid lipid particles that not only protect the curcumin from degradation by alkali, bile acids and other digestive enzymes through a protective covering, but that can also be reduced in size so that such particles can easily bypass the enterocytes, the cells lining the small intestines and enter straight into the blood. One such approach has been taken by scientists at the famed University of California in Los Angeles (UCLA). Working in their neuroscience laboratory, Drs Bruce Cole and Sally Frutchey were interested in how curcumin can prevent and/or reverse the sticky plaque that develops in the nerve cells (neurons) of many Alzheimer’s disease patients and decided to look at a non-piperine approach to enhancing bioavailability. After looking at over two hundred formulations, they finally developed the curcumin solid lipid particle as the best candidate to delivering curcumin into the brain. This formulation is called Longvida (see www.longvida.com) and was tested in bone cancer patients in India to see if it was more bioavailable than regular curcumin. Indeed the area under the curve (AUC) which is a measure of bioavailability, was between one hundred to two hundred times that of regular curcumin. The duration of the effect was greatly increased, as the formulation stayed in the system for a longer time since it was protected by the lipid covering. Clinically, the benefits to the patients were reduced episodes of pain, improved quality of life, and significant improvements in the remission rate. While this study was small, nonetheless the results did compare this new delivery system directly with curcumin. The study was repeated in 2012 at the University of Ohio when researchers gave a much smaller dose (80mg) to healthy patients and observed that curcumin was able to get into the brain in high enough concentrations and reduce the plaque formation within just thirty days! Finally, another key feature of this delivery technology over others was that the curcumin delivered to the active site was in the free curcumin form rather than the glucuronide or sulphated form which is typical of other delivery systems. This was discussed in part 1 of the bioavailability issue last time.
In conclusion, while piperine which is derived from the common food ingredient black pepper, the mechanism of inhibiting a defence system like the phase II enzymes to improve bioavailability may not be the best approach to take until more research into the long term effects are studied. Instead it may be a better option to use other technologies like the solid lipid particles that are proven to be safer and deliver higher amounts of active component to the target site.
Curcumin is the largest of the three curcuminoid components present in the root of Curcuma longa. Curcumin is probably the most widely studied natural product on the planet, and has a multitude of health benefits. These range from improving heart, liver, brain, and kidney function to preventing cataracts and gall bladder stones, having a powerful anti-cancer effect to being acknowledged as one of the strongest anti-inflammatory molecules on the market. However, curcumin has one drawback; it has poor bioavailability of around 2-3%.
Bioavailability is the amount of active molecule that reaches the target site, be it the knee joint, the nerve cell in the brain or the cancer tissue. Unfortunately, to measure the amount present at the actual target site is very expensive and labour-intensive, thus most researchers measure the amount of curcumin that is present in the blood as a surrogate marker of bioavailability. The procedure involves giving volunteers a known dose of curcumin-95, the highly purified curcumin molecule, and measuring the amount of curcumin present in the blood at 0, 1, 2, 4, 6, 8 and 12 hours. The procedure is then repeated, but this time using your improved formulation and then comparing the area under the curve (AUC). The difference is a relative measure of how many times the new formula is better (hopefully) than the standard curcumin-95.
The key issue is to measure and report free levels of curcumin in the blood. Unfortunately, it turns out that not all companies play by the same rules. Most companies just measure the total amount of curcumin present, whether it is in the free curcumin form or the various metabolites like glucuronide or sulphate. The reason is because if they measured free curcumin there would be very little present, as most of the curcumin has been acted upon or metabolized by the phase 2 enzymes and quickly converted into various metabolites. It is not to say that the metabolites are not active, indeed they most likely are, but it isn’t free curcumin, upon which most of the research has been conducted. Moreover, it is only the free curcumin that is able to get past the blood brain barrier (BBB) and into the brain to impact cognitive health. The metabolite forms aren’t able to get past the BBB due to their structure being altered through the addition of the glucuronide or sulphate groups. Measuring metabolites rather than free curcumin, and then claiming that their curcumin formulation is bioavailable, is not a justifiable conclusion. You are not comparing apples with apples.
Few companies have formulations that actually deliver free curcumin in the blood. One such product is Longvida, a patented product developed by the Alzheimer’s Lab at University of California at Los Angeles (UCLA). The researchers Drs. Bruce Cole and Sally Frutchey took years and tested over 200 formulations before coming up with their solid lipid curcumin particle. This delivery system has been clinically tested to confirm not only bioavailability but also bioactivity. First, in a human 2010 study in Mumbai (Gota et-al 2010), clinicians treated bone cancer patients with Longvida and found that it was over 100 times more bioavailable than curcumin-95! This is far better than any other product on the market which at best has reported a thirty-fold increase; even then it wasn’t the free curcumin form. In addition, the Longvida form had a much longer half-life than other forms. What this means is that the Longvida form stays in the body for a much longer time, and thus provides continued release to the cells and tissues.
But what does this hugely increased bioavailability actually mean in terms of health benefits? The Gota study actually reported improvement in various health parameters, such as reduced pain and nausea, improved appetite, and overall improved quality of life, as well as improving the remission rate from 2% to 19%. The second study, from Ohio State University, was published last year (Di Silvestro, 2012), and reported a significant reduction of the beta amyloid plaque, which is thought to be one of the culprits in the causation of Alzheimer’s disease. An even more remarkable finding was that this reduction was observed in just thirty days at a small dose of 80mg of Longvida curcumin!
It is important that we understand what bioavailability means, and know whether companies are reporting their findings based upon free curcumin, or a changed metabolite form.
Gota V et-al “The safety and Pharmacokinetic of solid lipid curcumin particle in osteosarcoma patients and healthy patients” Journal of Food Agriculture Chemistry 2010, 58; 2095-2099
Di Silvestro R et-al “Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people” Nutrition Journal 2012, 11:79;1-8
Chronic pain is one of the most common health concerns for which people seek medical treatment. Research suggests that up to 50% of the population may be suffering from some kind of chronic pain, with back pain being the most common.1 There are a number of possible causes that may contribute to chronic pain including: diet, posture, age, and injury. Vitamin D is another factor that is now being added to that list. Vitamin D deficiency is a very common occurrence, especially in people living in colder climates. It has been linked to numerous health conditions, one of those being musculoskeletal (MSK) pain.2
A recent study published in November of 2012 found that MSK pain is related to vitamin D deficiency, and supplemental vitamin D improved pain. The researchers found that 95.4 percent of the subjects were vitamin D deficient, and 85.5 percent of the subjects had improvement in pain with vitamin D supplementation.2 Of the subjects that responded to the treatment, post-treatment serum vitamin D levels were significantly higher than in the subjects who did not respond to vitamin D supplementation. The study concluded, “Treatment with vitamin D can relieve the pain in the majority of patients with vitamin D deficiency. Lack of response can be due to insufficient increase in serum vitamin D concentration. Reassessment of serum 25-hydroxyvitamin D concentration is recommended in nonresponsive patients”.2
This study confirms the results of a number of other studies that have found the same results. 3, 4, 5 The studies found that vitamin D deficiency may be responsible for generalized, non-specific pain, especially if it is resistant to manual and conventional treatments. A possible mechanism of why suboptimal levels of vitamin D can cause pain is that there is a reduction in serum calcium since vitamin D is responsible for its absorption from the digestive tract. This in turn stimulates the increase of parathyroid hormone which promotes the excretion of phosphate. Low levels of calcium phosphate lead to the deposition of un-mineralized collagen matrix on bony surfaces. When the collagen matrix hydrates and swells, it then causes pain by stimulating nervous endings on the periosteum.5
Due to the large proportion of the population that experience both chronic pain and vitamin deficiency, it would be prudent that healthcare practitioners and patients consider vitamin D levels a possible key-contributing factor. This may be especially useful in clinical settings such as pain clinics and chiropractic offices where there is a larger volume of [back] pain related cases.
The most recent data suggests that a person with less than 50 nmol/L of serum vitamin D is in a deficient state. The optimal levels are 100-160nmol/L. The most effective and accurate way to determine what dosage is required to reach optimal levels is to have your serum 25-hydroxyvitamin D assessed. The most recent guidelines from the American Endocrine Society suggest that 500-2000IU daily are effective to maintain adequate levels. For those that are deficient, 50,000 IU once a week for 8 weeks, or 6000 IU daily to achieve a blood level of vitamin D above 75 nmol/L is most effective and safe.6 Doses of 2000 IU or less are not able to effectively raise serum levels into the protective range.
Vitamin D can be a simple yet very effective therapy for chronic, non-specific pain if you are deficient. To determine if this may be contributing to your pain, have a qualified healthcare practitioner assess your serum levels and supplement appropriately to restore your optimal levels. Consider liquid formulations to increase the ease of achieving higher dosages. In medicine, sometimes the simplest piece is often the most important. Vitamin D once again forces us to go back to the basics in the quest to achieve pain free function.
1) Andersson HI, Ejlertsson G, Leden I, Rosenberg C. Chronic pain in a geographically defined general population: studies of differences in age, gender, social class, and pain localization. Clin J Pain. 1993;9(3):174-82
2) Abbasi M, et al. Is vitamin D deficiency associated with non specific musculoskeletal pain? Glob J Health Sci. 2012;1:107-11.
3) Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain.
Mayo Clin Proc. 2003 Dec;78(12):1463-70.
4) Al Faraj S, Al Mutairi K. Vitamin D deficiency and chronic low back pain in Saudi Arabia. Spine (Phila Pa 1976). 2003 Jan 15;28(2):177-9.
5) Holick MF. Vitamin D deficiency: what a pain it is. Mayo Clin Proc. 2003 Dec;78(12):1457-9.
6) Holick et al. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30.
Epidemiologists, researchers that look at populations and disease patterns have long remarked that the incidence of Alzheimer’s disease in India is significantly lower than in the US. One reason proposed for this huge difference may be because the Indian population has a high consumption of curcumin in their diet compared to their American counterparts.
Curcumin is the bright orange colouring agent that is the major active compound of the turmeric root and the main component of the masala the backbone of virtually every Indian dish. Besides imparting the rich colour to the food, curcumin is used as a preservative, for taste and more importantly as a medicinal ingredient.
Every Indian household uses ground up turmeric root as a quick remedy for various ailments from diarrhoea, to gastric upset, ulcers (internally and external), diabetes, liver problems, anti-parasite, injuries etc. In fact if someone happens to sustain an injury e.g. falling off a bicycle or a tree no doubt trying to either retrieve their kite and/or plucking the juiciest mangoes, mothers would quickly warm up some milk with added turmeric root and given copious amounts throughout the day until the swelling subsides. The reason for the milk is that Indian mothers have long known that boiling milk will enhance the effectiveness of the curcumin present in the milk.
It is now widely known that curcumin is poorly bioavailable meaning that very little actually gets absorbed and taken to the site of action i.e. the site of injury in the above case and thus large quantities are required. Quite large in fact upwards of 4 grams of curcumin and not the turmeric root (which contains around 1-2% curcumin) and in many cases 8-10 grams prove very little is getting absorbed! This poor bioavailability has hampered the wide use of curcumin as a drug and/or as a natural health product. Up till very recently this bioavailability issue has stalled any research of use of curcumin in Alzheimer research. That is until this year.
In October issue of Nutrition Journal Researchers at the University of Ohio used a special form of curcumin called Longvida which had previously been demonstrated ( Gota et-al 2010 human bone cancer study) to be more than 100 fold more bioavailable (the highest of any formulation on the market!) and is licensed from the famed UCLA (university of California Los Angeles). UCLA scientists tested over two hundred formulations before they came up with Longvida formula. Furthermore, the scientists also conducted a long term toxicity study to show that there are no untoward side effects of such a formula. Most products on the market rarely conduct such safety studies.
The researchers led by Dr Robert DiSilvestro looked at one of the marker of Alzheimer’s disease called Beta Amyloid Plaque (BAP)- a small protein that is now thought to be one of the two culprits in AD. The other culprit being tau protein tangles.
Using only 80mg of Longvida curcumin once a day to nineteen healthy subjects for just thirty days showed a significant decrease of BAP as well as other health markers like free radicals, triglycerides, sICAM (a marker for blood vessel health), U-CRC (a maker for inflammation) as well as raising nitric oxide (NO) a molecule thought to reduce AD (see previous article in this blog) and catalase an important enzyme for cell protection.
Many scientists working outside the natural product research are genuinely surprised that a natural compound can affect so many health markers and thus disease processes. Yet, this is typical of many natural products like green tea, polyphenols, resveratrol etc. but particularly curcumin that impacts over thirty or so pathways in the carcinogenic process alone.
The importance of such a study is several folds: first, the dose used was very small, second significant results were achieved within just thirty days of intake, third, there were improvements in health in other non-related AD markers like cholesterol, antioxidant capacity and inflammation.
Finally, the fact that these results were achieved with a healthy population suggests that even more significant results would be achieved in diseased population. Reduction of BAP within thirty days is unheard of. This study should be an impetus for a larger study.
DiSilvestro R A et-al “Diverse effects of a low dose supplement of lapidated curcumin in healthy middle aged people” Nutrition Journal 2012; 11-79
Gota V S et-al “Safety and pharmacokinetics of solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers”
J Agri Food Chem 2010;58:2095-2099
Alzheimer’s disease (AD) is an advanced stage of dementia which progressively worsens with time and is associated with a high degree of mortality. The disease is not part of normal aging, and is likely caused by various processes that damage nerve cells. Many clinical symptoms are associated with AD, including cognitive decline, memory loss, disorientation, language impairment and so on plus AD also has a pronounced effect on the family or their caregivers. In 2010 in the US alone there were over five million cases and over twenty million worldwide.
The cause of AD is not fully known but there is increasing support that amyloid plaque much like the cholesterol laden plaque seen in the arteries around the heart also builds up in the blood vessels in the brain. There are two schools of thought regarding AD causation. The first group believe a small peptide fraction between 40 and 42 amino acids long called amyloid-beta peptide (ABP), which is thought to be the major component of the amyloid plaque eventually forms aggregates outside the cells, adherents of this group are called the Baptists (from the beta). The second group believe in a different culprit called tau proteins which undergo chemical change called phosphorylation to form tangles within the nerve cells, these scientists are referred to a Toaists (from the tau). Whatever, the cause it is becoming increasingly clear that cardiovascular risk factors like high blood pressure, high cholesterol, obesity and diabetes which collectively are the hallmark of metabolic syndrome are intimately associated with AD. All these risk factors ultimately cause endothelial damage in the blood vessels in the brain and endothelial damage is strongly associated with AD.
But what causes either plaque and/or tangles to form in the first place?
Essentially, researchers have pieced together the following sequences of amyloid plaque formation. Nerve cells continually produce large amounts of long strands of a protein called APP (amyloid precursor protein). In AD the production of this protein is significantly accelerated and much more is produced than in normal brain cells. APP is then “cut” into smaller pieces or peptide fragments including ABP by various enzymes called secretases. The small ABP units clump together due to their “glue” like properties to form larger aggregates and “stick” together around the nerve cells literally “chocking” the cell to death. The body of course has a system to breakdown and clear these aggregates from the brain tissue however, in AD patients production of plaque exceeds clearance.
ABP is a nasty toxic molecule that not only directly kills nerve cells but also produces excessive amounts of free radicals which cause further damage and may assist ABP formation in a vicious cycle. Free radicals themselves cause much harm as they are quite damaging to nerve cell structures but also cause endothelial cell damage in the blood vessels.
Endothelial cells are one of the major sites of nitric oxide (NO) production. NO is one of the most important signalling molecules in the body which affects virtually every organ in the body allowing effective communication between cells and providing a wide-array of health benefits. It is a protective molecule that maintains immune, cardiovascular, nervous, kidney, stomach and intestinal, skin and other beneficial effects.
Lack of NO production by endothelial cells due to too much ABP aggregate formation and/or free radical generation only contributes to pathology of AD. Researchers have argued that if the NO production could be assured then AD would be significantly halted in its track. To test this hypothesis, researchers at the Mayo Clinic looked into the link between NO and AD through a number of elegant experiments and came to the following conclusions:
- When NO production is inhibited by using a known inhibitor, there was increased endothelial damage with ABP levels rising as expected accompanied by AD
- When NO production was increased by use of a known stimulator of NO production in an animal model of AD, the levels of ABP decreased and there was a significant improvement in memory of animals.
- Using genetic mice that cannot produce NO, the ABP levels rose in the brain tissue and there was significant brain damage compared to those mice that could naturally produce NO and were clear of AD
- NO seems to affect the production of ABP but does not affect its clearance suggesting that NO donors may work as preventative of AD rather than reversing AD.
These findings provide further support that keeping NO levels optimal may be beneficial strategy for prevention of AD and that NO donors like the inorganic nitrates may be useful.
AOR is the world’s first company to produce a range of NO products under their NOx 3,2,1 technology. Visit www.axiomahealth.ca for more information.
Austin S.A et-al “Endothelial Nitric Oxide modulates expression and processing of amyloid precursor protein” Circ. Res. 2010; 107:1498-1502
Antioxidants have been the hallmark of health and nutrition since the early 1970’s. Consumers, physicians and the media have been bombarded with the health benefits of antioxidants ever since. However, antioxidants came to prominence in the late 1800’s when first, the rubber and, later food companies found various antioxidants could prolong the life of their products. In the mid 1950’s Denham Harman, the father of antioxidant theory of ageing proposed that aging was a result of free radicals that were continually being generated in all the tissues! These free radicals originating from oxygen and nitrogen, like superoxide, singlet oxygen, hydroxyl, peroxynitrite etc. could react with the proteins, lipids, DNA and other cellular components causing destruction and ageing. One manifestation of ageing is the skin damage caused by UV light leading to skin or age spots.
Antioxidants come in all forms and guises like vitamins E and C as well as other non-vitamin compounds like Co enzyme Q10, to a host of polyphenols like quercetin found in apples and onions or resveratrol found in grapes, as well as some other compounds made within the cells of the body like glutathione and uric acid which is usually found circulating in the blood.
Classically, antioxidants are thought of as compounds that scavenge, quench or mop up the nasty free radicals, thus preventing their destructive nature. This however, is only one of the roles of antioxidant action.
Numerous researchers have studied the effects of consuming antioxidant-rich fruits, vegetables and nuts on the health of the population and have found a positive correlation. These epidemiological or population studies consistently confirm that the fruits and vegetables loaded with antioxidants reduce a host of diseases such as heart, circulatory, kidney, cataracts, arthritis and cancer to name a few.
These positive studies have resulted in the huge popularity of antioxidants as dietary supplements from capsules and tablets to creams and liquid beverages.
However, more recent research seems to challenge the view that free radicals are necessarily bad all the time. While the evidence supports the destructive nature of these free radicals, there is new and convincing evidence that these same radicals may actually be beneficial under certain conditions! How so you may ask?
The first point is that all antioxidants are a part of redox chemistry and as we all know, chemistry must be respected and all equations must be balanced. That is, antioxidants undergo simultaneous oxidation and reduction reactions. So for example, in order to perform their function, antioxidants will readily gain an oxygen atom or lose an electron and thus becoming oxidised in the process. The oxygen atom came from some place and likewise the electron has to go somewhere! The compound that supplied the oxygen atom and gained the electron originating from the antioxidant is reduced in the process. Of course the oxidized form can recycle back to its reduced and thus its original antioxidant form by losing an oxygen atom and/or gaining an electron. Thus antioxidants occur as both oxidised and reduced pair depending upon the environment they are in. These reactions are occurring continually.
The second point is that some antioxidants e.g. the flavonoids which are abundantly found in bright coloured fruits and vegetables and responsible in large part to their health benefits, once in the human digestive system quickly undergo the redox reaction and become oxidised or become pro-oxidant. This may even apply to certain vitamins like vitamin C and other endogenous antioxidants like glutathione. In other words, some antioxidants, once in the body, are in their oxidised form and perhaps that is how they are beneficial and not necessarily acting as antioxidants in the classical sense. Even pro-oxidants can have beneficial effects!
The third point is that free radicals themselves may not be bad as they have been portrayed. Free radical research has made rapid strides and researchers have made the startling discovery that neutralizing too many free radicals isn’t beneficial for the host. In fact it is a distinct disadvantage. It is a question of balance- not too high and not too low. Normally, free radicals may not be deleterious to our health and are readily dealt with or “mopped up” by our bodies, but under certain circumstances e.g. when there is excess production like cigarette smoke or ionizing radiation then damage may occur.
Vigorous exercise generates free radicals. If heavy doses of antioxidants (e.g. 1 gram of vitamin C and 400 iu of vitamin E) are taken immediately before or after, then the positive benefits of exercise are blocked! For example glucose isn’t taken up by muscle cells effectively. These results suggest that exercise generated free radicals have their own health benefits.
Here are some positive roles that free radicals may play:
- Free radicals act as signalling molecules whereby they can communicate with other players (e.g. white blood cells and messenger molecules like cytokines and chemokines etc.) and relay messages to and fro. This is important as the body relies on extensive channels of communication to deal with constant danger it faces.
- In lower concentrations free radicals are required for good “housekeeping” and ensuring that the body functions properly.
- Free radicals may actually come to our rescue especially during an attack by hostile invaders with which we are constantly exposed to. In fact, when our immune cells confront these bacteria, fungi and viruses they deliberately unleash free radicals of their own by a process called “oxidative burst” thereby overwhelming the invaders and destroying them in the process. That is why we use peroxide at the site of injury. Remember, if free radicals in excess can damage various parts of our cells, they can also destroy invaders by the same mechanism! In fact this is how free radicals help protect our bodies, by “neutralizing or scavenging” the microbes. One big advantage in using free radicals as a defense system is that the invaders are unlikely to develop any resistance to free radicals. In the 1980’s it was demonstrated by researchers that one of the mechanisms of action of antibiotics was through generation of free radicals. It seems that certain antibiotics actually mimic our immune cells by fighting-off infections by generating free radicals. More recently, pharmaceuticals have been developed that deliver free radicals under controlled conditions to the site of action in conditions like rheumatoid arthritis, ageing and other diseases with some success. This field is in its infancy but offers exciting possibilities. Think about it, free radicals used as a therapeutic option for disease treatment!
- Free radicals stimulate various genes e.g. Antioxidant Response Elements (ARE) to help switch off the production of important inflammatory players like NF-kappa B, TNF-alpha and switch on various helpful messenger molecules like chemokines and cytokines.
- Ironically, free radicals help switch on the production of antioxidants themselves like super oxide dismutase (SOD), catalase and glutathione peroxidase, enzymes that our cells use to maintain their healthy status.
When excess antioxidants are taken, free radical concentrations become dangerously low and this can cause detrimental health issues. Recent examples include selenium and diabetes and high concentrations of various antioxidants like green tea, curcumin and resveratrol having toxic effects in both test tube and in animals. Again more is not necessarily good for us.
What are the repercussions of this discovery? Many questions remain e.g. what is the ideal antioxidant dose to take? how do different antioxidants interact with one another when taken together? When to take the antioxidants? Should one take antioxidants at the beginning of an infection or later? Likewise when to take during a bout of inflammation? Remember, free radicals are being generated continually and, is taking one a day or twice a day antioxidant regimen effective? Should antioxidants be taken during radiation and/or chemotherapy? More research is needed.
It is likely that high doses of antioxidants may not be a good idea as we are likely to unbalance the fine-tuning of the redox chemistry and thus fail to take full advantage of antioxidants and free radicals themselves. Sorry Linus, we have to disagree with you on the mega supplementation. Balance is the name of the game!
For over twenty five years grape fruit seed extracts have been widely used as antibacterial, antiviral, antifungal and as a healthy alternative to the pharmaceutical/chemicals on the market. So prevalent has the use been, that one sees sprays, wipes, towelettes, washes, drops and even oral capsules! The manufacturers of these extracts have aggressively promoted their use for all manner of uses as safe and natural.
Earlier this year, a startling study by the American Botanical Council, a non-profit US organization was released. All grapefruits seed extracts they tested were contaminated with synthetic and widely used chemicals and there were no exceptions! Furthermore, the natural grapefruit seed extract they manufactured in their own labs were devoid of any antibacterial activity. What does this mean? It means that ALL the grapefruit seed extract products on the market that have antibacterial properties only do so if they are contaminated with synthetic chemicals. The bottom line it is the synthetic contaminants themselves are responsible for the antibacterial effects and there is nothing natural in these extracts that has antibacterial activity.
These findings are not new. In fact two separate groups of Japanese researchers actually reported similar findings over twenty years ago! Unfortunately, their publications were in Japanese and were largely inaccessible to the Western media. Both groups of Japanese scientists reported that all the commercial grapefruit seed extract products they tested contained the synthetic methyl hydroxyl benzoate, tricolosan and benzathonium chloride. All three chemicals were widely used disinfectants, preservatives and biocides. Later, other researchers in Europe and the US published similar reports.
When the manufacturers of the grapefruit seed extract were challenged to explain the results, one manufacturer actually said that their proprietary extraction process using the grapefruit seeds, hot water, ammonium chloride and hydrochloric acid, produced novel antimicrobial products. This notion was quickly dismissed by some of the leading organic chemists as “nonsensical” since there was no known organic chemistry pathway that would generate these three chemicals. They had to be deliberately added!
Even more troubling is the fact that over the years the manufacturers have changed the chemicals to benzalkonium chloride so as not to be caught and/or due to newer detection instruments. The manufactures are trying to stay one step ahead of the analytical methods. The evidence is pretty damning! Other researchers having conducted an extensive literature search but have failed to find any historical record for use of grapefruit seed extracts for any medicinal uses including as natural disinfectants. Furthermore, there is no documentation in any herbal compendium, pharmacopeias, PubMed database or any authoritative herbal textbooks worldwide for such use.
All these synthetic chemicals have toxicity issues for topical and especially oral use, ranging from skin irritation, burning, damage of skin membrane to genetic or reproductive toxicity to nerve and liver damage in animals.
Adulteration: a key problem in the natural health Industry.
The grapefruit seed extract debacle is just one example highlighting the fairly prevalent practice of adulteration. In this case, manufacturers sold a natural product that had no antibacterial property. They added inexpensive but powerful chemicals and sold the product at expensive prices. This type of adulteration is an example of economically motivated adulteration. But there are many others types of adulteration. For example, the need to use a cheaper alternative to the more expensive herbs like saffron, or even common ingredients like black cohosh and peppermint. It can also be due to supply issues and/or restrictions in export of herbs in danger of extinction e.g. boswellia gum resin used to makes nature’s most powerful anti-inflammatory. Most recently, the Monsoons in India resulted in a fairly low crop yield for turmeric root, the key ingredient used to make the popular curcumin products. Some manufacturers deliberately added synthetic curcumin and passed it off as natural curcumin.
Another reason for adulteration is public perception. Most North Americans view that the majority of the ingredients used in natural health products originate from the US (approximately 77%), while 10% of the ingredients come from China and 7% from Europe. Yet, the fact of the matter is that over 60% of the ingredients actually come from China and only 12% come from the US. This means that the majority of what North Americans believe comes from domestic sources actually comes from Asia!
There is a constant pressure for manufacturers to cut corners on purity, strength and identity and offer their consumers a low cost product. But such a strategy can come at a terrible cost. The significant side effects due to adulteration can be harmful as evidenced by the recent case of geranium oil adulterated with DMAA (1,3 dimethylamylamine), which was sold as a sports workout products. But DMAA is not a natural product and toxicity has been reported.
The old adage is true, you get what you pay for but it also highlights the continual need for consumers to be weary of what they are buying.
A sure fire way to assess the quality of your supplements is to check if the vitamins and mineral are in the most biologically active and absorbable forms. Most formulations contain vitamins and minerals in their most commonly used and often cheapest form. To the untrained eye this may not seem like a big deal especially if the cost of the formulation seems like a good bargain. Allow me to shed some light on why the most active forms of vitamins and minerals can have a substantial benefit to your health and can sometimes be the difference between on effect vs. a profound shift in your health.
Modified from http://www.rondellen.net
The body’s physiology is intricate and complex and it often converts orally absorbed nutrients a number of times before it is in a form that is useable. A good example is the amino acid tryptophan. It has been traditionally used as precursor to the neurotransmitter serotonin however it first must be converted to 5- hydroxytrytphan (5-HTP) before serotonin is formed. It is advantageous to supplement with 5-HTP since it is a step closer to the desired molecule.
In other cases certain forms of vitamins are absorbed better in our digestive tracts than others. A good example is calcium. The most commonly used form of calcium is calcium carbonate (minerals are supplemented as combination compounds called salts or chelates to maintain stability). Its absorbability is similar to calcium citrate but it requires an acidic environment to be optimally absorbed so it must be taken with meals. Furthermore, acid reducing medications (PPI’s) reduce its absorption since they reduce stomach acidity (PPIs used for more than 12 months cause a magnesium deficiency). Calcium citrate does not require an acidic environment to be absorbed so a higher percentage of absorption can be achieved in people with low stomach acid (which is actually quite common).
Another great example is a form of B1 (thiamin) called benfotiamine. B1 is essential in preventing the damaging effects of high blood sugar in diabetics. Many studies have shown it has a powerful effect on reducing nerve pain and damage to sensitive tissues such as the capillaries in the retina. Although benfotiamine is not lipid soluble, it has been shown to have very good bioavailability. This is because benfotiamine is converted into a more fat-soluble compound by enzymes present in the cells of the intestinal mucosa. This allows it to pass easily through cell membranes and become absorbed. Once absorbed it travels back to the liver where it is converted to thiamine and released into the bloodstream. This means that benfotiamine is better absorbed than thiamin itself. Thiamin absorption from benfotiamine has been shown to be about five times as great as from conventional thiamin supplements (1).
Certain vitamins require specific enzymes to convert them into the active forms within the body. Two classic examples are vitamin B6 and folic acid. Vitamin B6 (Pyridoxine) is absorbed in the intestines and converted to its active form, pyridoxal-5'-phosphate, in the liver by the enzyme pyridoxal kinase. However, in some people their liver function is slow or impaired so the production of P5P will be limited. One study found that in patients with impaired liver function, only 33% responded to pyridoxine hydrochloride supplementation with an increase in plasma P5P, where as all of the patients receiving P5P supplementation experienced an increase (2). P5P is beneficial for the treatment of depression since it is an essential cofactor for neurotransmitter production, improve carpal tunnel syndrome and it can reduce the harmful amino acid homocystine, which can impair the production of glutathione and predispose a person to multiple health conditions including Alzheimer’s disease, sudden cardiac events and many more.
Folic acid is essential for DNA and RNA formation, genomic maintenance, and red blood cell production. A deficiency during pregnancy was found to cause neural tube defects in infants so it was mandated by governmental agencies that folic acid should be fortified in standard foods such as bread and cereals. Natural folates are found in dark green leafy vegetables (spinach, kale, mustard greens, turnip greens) and other vegetables and their absorption is approximately 50% less than that of supplemental folic acid.
Even though folic acid has good intestinal absorption its conversion is to its active form, 5-Methyltetrahydrofolate (5-MTHF) hinges on the enzyme methylenetetrahydrofolate reductase. The family of genes that are responsible for the production of this enzyme are often malfunctioning in a large proportion of the population especially those that are chronically ill or have neurodevelopmental disorders (such as autism). The figures are not exact but experts and studies both report that anywhere between 50-75% of the population have at least one or two mutations of the MTHF genes. This means that these people have a sluggish or impaired formation of 5-MTHF, which plays a key role in cell and DNA repair, detoxification, homocystine metabolism, and cancer prevention. This predisposes these people to cardiovascular disease, autoimmune disorders, mental and neurophysciatric illness such as bipolar and schizophrenia and neurodevelopmental disorders such as autism.
Supplementing with the 5-MTHF form of folic acid can bypass the impaired genes and enzyme and carry out the essential functions. As a note, folic acid (or 5-MTHF) should be supplemented with vitamin B12 since they work in together in the stimulating neurological pathways and homocystine detoxification, and folic acid supplementation can hide the symptoms of B12 deficiency.
Hopefully you have gained an appreciation of how supplementing with the most biologically active forms of certain vitamins not only provide superior action and health benefits but also end up providing better value for your dollar since the dose is usually smaller and absorptions is better. Clearly, not all supplements have been created equal since there are many products that still use poorly absorbed forms. So if you want superior benefits from your supplements look for products that use active forms and don’t cut corners on your health.
- Loew D. Int J Clin Pharmacol Ther. 1996 Feb;34(2):47-50. Pharmacokinetics of thiamine derivatives especially of benfotiamine.
- Labadarios D, Rossouw JE, McConnell JB, Davis M, Williams R. Gut. 1977 Jan;18(1):23-7. Vitamin B6 deficiency in chronic liver disease–evidence for increased degradation of pyridoxal-5'-phosphate.
An antioxidant is any substance that promotes health by removing reactive species that may otherwise exert harmful effects in the body. The origins of the biological effects of antioxidant goes back to antiquity e.g. the time of Egyptians as evidenced by the remarkable preservation of dead bodies in part due to the use of plant polyphenols in the embalming process. Years later such antioxidants were considered “elixirs” of youth and the interest in antioxidants began to spike. Since the 1980’s, both the number of research papers on the subject and the number of natural products on the market with an antioxidant claim have grown exponentially. Today, the term antioxidant is so widely perverse that it has become an almost meaningless term!
There are tens of thousands of natural compounds that have demonstrated antioxidant activity and hundreds of thousands of natural products (dietary supplements) on the market with an antioxidant claim.
The plant and marine kingdom are full of natural compounds with antioxidant activity. These include flavonoids; a huge category that is further subdivided into six subcategories which includes the colourful anthocyanins, which gives berries their striking colours; quercetin, which is abundant in apples and onions and also polymethoxy flavones from citrus fruits. Polymethoxy flavones, especially, are generating much excitement due to their potent anti-cancer activity. Resveratrol, is another ingredient abundantly found in wine and other herbs that is associated with increased life span at least in yeast and worms and with possible implications for humans.
Similarly, various carotenoids including zeaxanthin from paprika to lutein from marigold flowers to fucoxanthin from the algae offer exciting possibilities for health. Likewise, the powerful curcumin from the turmeric root which is widely used in Asian cuisine to catechins from green tea all exhibit powerful antioxidant effects.
All these natural chemicals are able to quench the nasty free radicals generated from oxygen, nitrogen and sulphur, all of which are so reactive they cause damage as soon as they come into contact with the various compounds in tissues of the body. This includes the DNA found in the nucleus, lipid molecules of cell membranes and proteins and amino acids that form the structural components of skin, joints, nerve cells etc.
Antioxidants have a long history of use in the nutrition and the food industry. The traditional understanding has been that antioxidant chemicals promote health by removing these reactive species. According to this definition, most reactive species were considered to be harmful, implying that maximizing antioxidant concentrations could minimize the risk of disease. The public has become too familiar with the term antioxidant and equates it to a chemical that is good for our wellbeing. Antioxidant foods, drinks cosmetics and supplements abound.
Extensive research has found that quenching these radicals is normally associated with good health. After all, if you neutralize these reactive species one can mitigate molecular and cellular damage.
Physicians and the natural health industry have enthusiastically embraced antioxidants overwhelmingly, to the extent that antioxidants are recommended for any and every disease.
From a commercial, retail and a physician’s viewpoint a major difficulty occurs- how to select the best antioxidant from a list of tens of thousands? Various assay systems have been developed to measure or assess the antioxidant capacity of such molecules. These include: total radical-trapping antioxidant parameter (TRAP), trolox equivalent antioxidant capacity (TEAC), ferric reducing antioxidant power (FRAP), etc. One popular assay system called the Oxygen Radical Absorbing Capacity or ORAC is a widely used assay. Essentially, the compound being tested (the antioxidant) is added to a liquid mixture containing a fluorescent dye and a known oxidant (the nasty free radical) in a test tube. The oxidant causes the dye to fluoresce. The antioxidant combats this action and the rate of disappearance of the fluorescence is a measure of the ORAC.
ORAC is widely used by supplement and food companies. Labels and charts are often created that show the ORAC “potency” of their product or food compared to their competitor and have blatantly advertised this “fact” to the general public with the mindset that the higher the ORAC value the more potent the antioxidant and thus superior and healthier the product. An ORAC value of less than a thousand is regarded as “low” antioxidant potency while anything between the ranges of 2,000 to 5,000 is considered an “average” potency and anything around a value of 10,000 is considered highly potent.
ORAC values are being used by many manufacturers to differentiate their products. From berry extracts to tea bags, antioxidant claims are ripe. In fact, antioxidants are becoming an ORAC race, the more ORAC you could measure the better. However, something is amiss here. First, the ORAC test is a chemical assay, it is not a biological assay! It takes place in a test tube, an isolated system under conditions that are far removed from the real life situation of a dynamic biological system in our bodies. Moreover, the test tube conditions are unrealistic when it comes to the pH, temperature, concentrations of antioxidants used etc. What happens in people cannot be modeled under test tube conditions. There is a big difference.
Second, ORAC is limited to one reactive oxygen species, the peroxyl radical, it does not measure the quenching of other oxygen species like the hydroxyl, superoxide and singlet oxygen. Finally, ORAC does not measure activity against other non-oxygen free radicals like nitrogen and sulphur. In fact the peroxynitrite free radical aptly termed ONOO is particularly nasty and damaging.
Recently, one company actively marketed their black tea extract as having an ORAC value of up to 1,000,000! What does such a figure even mean? Is such a product 100 times more potent than a compound with an ORAC value of 10,000? Does it mean that one can take it at 100 times a lower dose? Will it be 100 times more effective?
In reality there is no dose-response relationship, meaning that ORAC values have no significance to physiological effects or health benefits and thus are biologically irrelevant. Just increasing ORAC value provides no guarantee of greater health benefit. It is pure marketing. No wonder regulators world-wide do not equate antioxidant claims with any health benefits. Recently, the Indian FDA confiscated Brooke Bond tea from Unilever India which made a claim, “A rich source of antioxidant flavanoids that protect the cells and tissues of the body”. Likewise China does not permit any health claims to be associated with antioxidant activity. In the opinion of European Food Agency (EFA), “No evidence has been provided to establish that having antioxidant content or activity has any beneficial physiological effect”. Furthermore, even the induction or stimulation of endogenous antioxidant enzymes like catalase or SOD etc alone cannot be considered as evidence for claims of an antioxidant defense system.
One US expert on antioxidants has gone as far as demanding that the term antioxidant should be banished from food and supplement labels with more specific claims about health benefits. There seems to be considerable support for such a proposition at least from the scientific community but unfortunately, supplement and food companies still persist in such nonsense!
It is time for food and supplement companies to step up to the plate and substantiate implicit and explicit claims of performance based on antioxidant performance. This can only be achieved by assay systems that are significantly better than ORAC, like the recently developed cellular antioxidant activity (CAA) assay or better still linking antioxidant with a specific health benefit.