Turmeric has been used as a spice and for medicinal treatment for over 4000 years in India for treatment of arthritis, gastrointestinal discomfort, and as an anti-inflammatory agent1. Turmeric contains only 2-5% of curcumin by weight, so consuming turmeric or a powdered turmeric supplement in order to benefit from the effects of curcumin is an ineffective strategy.
In the present day, curcumin is extracted from turmeric to obtain a more purified source of curcumin. Typically a curcumin extract is standardized to contain no less than 95% curcuminoids. The curcuminoids are a family of three compounds – Curcumin, Demethoxycurcumin, and Bisdemethoxycurcumin.
Curcumin is the most abundant of these curcuminoids, composing of roughly 77% of the total curcuminoids, with demethoxycurcumin comprising about 17%, and bisdemethoxycurcumin comprising about 6%.
Simply taking a curcumin extract supplement will not provide any benefits, with one human study demonstrating a dose of 2 grams taken not leading to any elevation in serum levels, meaning the amount of curcumin actually absorbed was very small, if anything at all. One easy way to significantly improve its bioavailability is to consume it with black pepper extract, otherwise known as piperine. The combination of pairing curcumin with piperine is well researched, and has been shown to increase bioavailability of curcumin by up to 20-fold3. This coadministration with piperine also lead to a decrease in the rate of elimination and clearance. This effect on increased absorption with piperine is seen due to piperine’s ability to inhibit the activity of the enzyme CYP3A4, the major enzyme responsible for Phase I drug metabolism; which in this case would lead to the reduction of the 4 double bonds in curcumin4, leading to formation of reduced curcuminoids such as tetrahydrocurcumin, which will be discussed further below.
Curcumin also has improved bioavailability when paired with the flavonoid Quercetin, due to quercetin’s ability to inhibit the P-glycoprotein efflux pump in the intestine. Combinations of curcumin with piperine and quercetin have been employed successfully for the bioenhancement of curcumin0.
Another way to increase bioavailability of curcumin extract is to consume it with a high fat meal, which will slow the transit time in the gastrointestinal tract and improve the absorption. One study showed this effect to lead to a 29-fold increase in absorption compared to curcumin extract alone5. However, it is important to note that even with the 29-fold increase, plasma concentration of curcumin was still not enough to see the anti-inflammatory benefits of curcumin.
Although combining a curcumin extract with either piperine or dietary fats led to 20-29-fold increases in bioavailability, it was still not enough to reap the benefits of curcumin.
Micronizing curcumin increases the surface area of the particles, thus leading to improved water solubility and increasing bioavailability, this method changes the actual type of curcumin being ingested, so its bioavailability can further be increased by piperine. Micronized curcumin taken by itself showed a 14-fold increase in bioavailability compared to curcumin alone6.
The most effective methods for increasing bioavailability have been shown to be nanosuspensions and carrier based nanosystems. Methods such as placing curcumin in a cyclodextrin complex exist, and in doing so are able to significantly enhance the water solubility and bioavailability of curcumin7.
Transporting nanoparticles of curcumin through the gastrointestinal mucosa (mucous membrane of the stomach) permits significant bio-enhancement. There are several different nano-based delivery systems which can be used for curcumin, such as liposomes, solid lipid nanoparticles, micelles, and microemulsions
Although these delivery systems differ in the way they are produced and their effectiveness, their goal is the same: to reduce the particle size of curcumin, and to increase lipophilicity of the curcumin in order for it to be absorbed through the intestinal lymphatic system8.
Microemulsions of curcumin can be formed by mixing oil, water, and surfactants with the curcumin. These microemulsions show a 22.6-fold increase in bioavailability compared to curcumin suspension9.
Liposomes differ from Solid lipid nanoparticles and micelles because they have the ability to encapsulate and deliver water soluble drugs or supplements, as well as fat soluble products like curcumin. Liposomes have an outer fat soluble shell and a water soluble core, and can be layered like an onion with alternating fat and water soluble layers, the more layers the liposome has, the larger it is (some are over 1000 nm), and the less of a suitable drug delivery system it becomes. Due to their generally larger size compared to micelles, they are not as effective in delivering a fat soluble product like curcumin. This can be shown in studies comparing the bioavailabilities of liposomes vs micelles, where curcumin micelles demonstrated a 117-fold increase in bioavailability 10, compared to a curcumin extract. Studies done on liposomal curcumin demonstrated only a 7.8-fold increase in bioavailability compared to curcumin suspension0.
Solid lipid nanoparticles (SLNs) are a new pharmaceutical delivery system with a solid lipid core. SLNs of curcumin have been formulated being only 20-80nm in size11. SLNs are different than micelles in the fact that they are solid lipids at body temperature compared to being oils, with a surfactant coating on the outside making them more stable than liposomes or microemulsions12 This difference makes SLN based curcumins the most potent and bioavailable form of curcumin to date, with up to 155-fold increases in bioavailability being documented in clinical studies, SLN curcumin edges out micellar curcumin in superior bioavailability, as the difference in their nanostructures would indicate13.
SLN compounds are able to have prolonged blood circulation, as well as the unique ability to permeate the blood brain barrier, resulting in improved brain delivery compared to other nutraceutical delivery systems16.
SLN Curcumin can be applied as a topical gel, and is able to permeate the skin for pigmentation and dermatitis treatments14.
Even though they are lipid based, SLN curcumin formulations are able to mix well in water due to their small particle size.
One example of a SLN curcumin formulation is Longvida® Optimized Curcumin, which is also the only form of curcumin that has been shown in clinical studies to cross the blood-brain barrier, and a daily dose of 400mg shows notable improvements in brain function after just one hour15. Evidence shows that Longvida can be up to 285x more bioavailable and 7 times longer lasting than a standard curcumin extract6. Leviathan Nutrition’s overall health product – IRE has 750mg of Longvida® Optimized Curcumin per serving, meaning that even with half a serving per day, users will still be getting a clinically effective dose.
Curcumin’s numerous benefits can be attributed to its unique molecular structure. The structure of curcumin is the result of two structures of ferulic acid being joined together by a methylene bridge.
Curcumin has three important aspects of its structure which are responsible for the majority of its benefits: an aromatic o-methoxy phenolic group, α, β-unsaturated β-diketo moiety, a seven carbon linker with a methylene group (the only fully saturated carbon on curcumin’s main structure)17. In order to understand these portions of the structure of curcumin, please see the diagram below
The two o-methoxyphenol groups on each side of the molecule, as well as the methylene carbon in the middle of the structure contribute to the antioxidant activity of curcumin, where electrons or hydrogen atoms are donated to reactive oxygen species. The unique ability for the β-diketo moiety to undergo a process known as keto-enol tautomerism, along with the long chain of carbons linking curcumin together both assist in curcumin’s ability to form covalent or hydrogen bonds to a large number of molecules in the human body, such as enzymes, carrier proteins, inflammatory molecules, DNA, and RNA
The two carbonyl oxygens can bind metals (known as chelation), giving curcumin its ability to remove toxic heavy metals such as arsenic, lead, and mercury from the body18. Each of these important functional groups can be modified to improve certain properties in the structure of curcumin, creating drugs known as synthetic analogs of curcumin, which are widely researched for their application in cancer treatment.
There are hundreds of different analogs of curcumin which have been synthesized in order to amplify the known properties of curcumin, two of the most popular analogs are known as EF24 and HO-3867.
In these compounds, the aromatic rings are substituted with Fluorine atoms to give stronger electrostatic interactions than the parent compound, as well as the center of the molecule now having a hydrogen for donation attached to a nitrogen or oxygen as opposed to the methylene carbon that curcumin is known for. These adjustments in the structure lead to greatly increased bioavailability, anti-inflammatory, and anti-cancer effects20. To demonstrate these effects, EF24 has been shown to be 10 times more effective, and less toxic than the anticancer drug cisplatin21
Since these compounds have been chemically altered and do not occur in nature, they are only available as drugs and are not allowed to be sold as dietary supplements.
Another class of notable compounds derived from curcumin (and the curcuminoids) are tetrahydrocurcumin (and the tetrahydrocurcuminoids). Unlike the synthetic analogs of curcumin, these tetrahydrocurcuminoids are available as dietary supplements, since they are a direct result of the metabolism of curcumin itself, these compounds are simply the curcuminoid structures with the two double bonds reduced on the seven carbon linker.
Tetrahydrocurcumin is white in color, which makes it a popular choice for lotions compared to the yellow-colored curcumin. Tetrahydrocurcumin is 3 times more bioavailable than curcumin, and has stronger anti-oxidant effects than curcumin. On the contrary, tetrahydrocurcumin lacks anti-inflammatory and pro-oxidant activities. Curcumin is also able to bind to more molecules in the body, including DNA, while Tetrahydrocurcumin cannot. The targets of curcumin vs tetrahydrocurcumin are summarized in the following figure:
To summarize, Tetrahydrocurcumin has better anti-oxidant effects and bioavailability, as well as its white color being useful in its application in lotions and creams, but the anti-inflammatory, pro-oxidant, and its ability to bind to many targets of curcumin make it a better, more versatile compound overall.
Understanding the metabolism of curcumin in the body gives us a clear understanding for the poor bioavailability of curcumin. Curcumin is mostly metabolized in the liver. Curcumin is metabolized by Phase I and Phase II drug metabolism, where it either gets reduced or converted to curcumin glucuronide and curcumin sulfate. These two metabolites are a result of Phase II metabolism, and are inactive metabolites.
However, some of the reduced metabolites of curcumin as a result of Phase I metabolism, such as tetrahydrocurcumin which was discussed above, do have some active properties.
There are some methods to improve this metabolism, the first and most effective method is by encapsulating the curcumin molecule in a lipid soluble nanocarrier, such as a liposome, micelle, or solid-lipid nanoparticle, with the latter showing the greatest stability and effectiveness. Doing this to the curcumin makes it fat-soluble enough to be absorbed through the lymphatic system and enter systemic circulation where it is now active. Being absorbed by the lymphatic system will bypass metabolism through the liver entirely, resulting in none of the curcumin being degraded into curcumin glucuronide, sulfate, or other reduced forms.
Another method of improving the bioavailability of curcumin is by adding piperine. The reason why this enhances bioavailability is because piperine can inhibit the activity of the enzyme CYP3A4 as well as glucuronidation, which will slow down the phase I metabolism and the amount of curcumin converted to inactive metabolites.
In drug metabolism, the P-glycoprotein efflux pump is responsible for transporting certain compounds out of the membrane to be excreted from the body.25 The addition of Quercetin, which has been shown to inhibit activity of P-glycoprotein, can further improve the bioavailability of curcumin if it is being metabolized by the liver26.
However, with the methods above regarding piperine and quercetin, it is important to note that this route still undergoes liver metabolism, so there is still some Phase I and II metabolism taking place as these methods are not completely able to inhibit metabolism.
Curcumin exhibits cardiovascular protective effects due to its ability to protect against oxidative stress, apoptosis (cell death), inflammation, as well as its ability to decrease cholesterol27. The effect of curcumin on the heart has been studied in situations involving: cardiac hypertrophy, heart failure, drug-induced cardiotoxicity, myocardial infarction, atherosclerosis, abdominal aortic aneurysm, stroke and diabetic cardiovascular complications28
Curcumin preserves cardiac function and promotes proper cardiac muscle tissue repair after heart attack29
Curcumin has been shown to prevent and reverse cardiac hypertrophy (enlarged heart)30. This particular effect of curcumin can prove to be useful in athletes such as bodybuilders, who use compounds that contribute to an enlarged heart, which becomes a major health issue in these athletes later on in life.
Patients taking 150mg of a standardized curcumin supplement twice per day experienced an improvement in endothelial dysfunction (a condition where the lining of the arteries fails to function normally) that was comparable to atorvastatin, a statin prescription drug used to treat cholesterol.31
Curcumin has demonstrated the ability to protect the liver by lowering enzyme values, lipid peroxidation, increasing activity of the master antioxidant glutathione, and other mechanisms after the liver was subjected to damage32.
Curcumin also protects the liver from damage from drinking alcohol, mainly by raising glutathione levels33.
Curcumin protects the kidneys in chronic kidney disease by reducing leakage of pro-inflammatory molecules through the intestine by increasing intestinal alkaline phosphatase, this prevents the ability of these pro-inflammatory molecules from entering the circulatory system34.
Curcumin improved creatinine clearance, which is a main indicator of proper kidney function
The protective effects of curcumin on the kidneys has been thoroughly studied in cases involving: diabetic nephropathy, chronic renal failure, ischemia and reperfusion, and nephrotoxicity induced by toxic compounds35
Curcumin taken at a low dose has been shown to lower LDL cholesterol, overall cholesterol, as well as triglyceride values36.
Curcumin may have significant effects on raising HDL cholesterol values if it is taken as a more bioavailable form than a typical curcumin extract37
Because it has higher bioavailability in the gastrointestinal tract compared to other organs, curcumin has been studied in diseases such as inflammatory bowel disease, colorectal cancer, and hepatic fibrosis38.
Curcumin prevents gastrointestinal induced ulcers and can be used for ulcer treatment39.
Curcumin displays pre-biotic like activity, resulting in positive changes in gut flora40.
Curcumin has been shown to be a more effective anti-inflammatory than NSAIDs such as aspirin and ibuprofen41 and even demonstrated effects rivaling that of corticosteroid treatment without the side effects.42
Curcumin has been shown to slow the disease progression of osteoarthritis, reduce pain, increase physical function, and quality of life in many clinical studies involving human patients43.
Curcumin can protect neurons and prevent cell death after spinal cord injury44.
Curcumin is able to reduce the amount of water content in the brain after cerebral ischemia/reperfusion injury (when blood flow is restricted to the brain causing damage, and blood flow is then returned)45.
Curcumin shows promise for treatment of brain cancers such as glioblastoma46.
Curcumin is able to increase levels of the omega 3 fatty acid DHA in the brain47, taking supplemental DHA itself is not able to increase DHA levels in the brain48, making this a unique use for curcumin in humans.
Curcumin can also protect the brain against toxic effects caused by fluorine49.
A highly bioavailable curcumin supplement also has nootropic effects, A dose of 400mg/day of Longvida® optimized curcumin resulted in a significant improvement in cognition and mood in as little as an hour in patients50
As mentioned before, Water soluble curcumin cyclodextrin complexes used to make eyedrops showed great absorption for a once daily treatment for damaged retina51. Curcumin has been shown to be an effective treatment for dry eye disease52.
Curcumin can be used as a treatment for cataracts due to its ability to prevent the accumulation of free radicals53.
To summarize all of the information given in this article, curcumin is one of the most effective nutraceuticals to exist, with a unique molecular structure giving it powerful properties as an anti-oxidant, anti-inflammatory, and the ability to remove heavy metals from the body. Previously, curcumin was not able to display these many health benefits in humans due to poor bioavailability. The innovation of nanotechnology has allowed more bioavailable forms of curcumin to be made and deliver the benefits of this nutraceutical to humans, with solid lipid nanoparticle systems such as Longvida® being the most effective (up to 285x more bioavailability and 7x longer lasting than curcumin extract), and micelle encapsulated forms of curcumin a close second. This is due to both formulations being absorbed through the lymphatic system bypassing liver metabolism. Consuming a curcumin extract with piperine or a high fat meal can increase bioavailability by 20x-30x, but is still not enough to see the anti-inflammatory effects of curcumin; which is why it is important to use a solid lipid nanoparticle or micellar curcumin formulation to reap the full benefits. Longvida® is the only form of curcumin to be able to cross into the blood brain barrier and enhance cognitive function immediately after taking it.
Curcumin has proven use in humans aiding in digestion, joint health, kidney, liver, heart, eye health, reducing cholesterol levels, and shows promise in cancer treatment. Curcumin is able to reduce the size of an enlarged heart, making it a promising supplement for athletes who have taken PEDs. Curcumin has stronger anti-inflammatory properties than NSAIDs, and also rivals some corticosteroids in effectiveness without the side effects. Synthetic analogs of curcumin are being made to provide effective cancer treatments. Some metabolites of curcumin, such as tetrahydrocurcumin, retain some of the effective properties of curcumin, but do not display many of curcumin’s other benefits. Pairing curcumin with other ingredients such as quercetin and resveratrol show enhanced effects and improved absorption of all of these ingredients.
In Leviathan Nutrition IRE, we pair Curcumin with piperine, resveratrol, and quercetin for high inhibition of CYP3A4 enzymes and P-glycoprotein efflux pump in the intestinal mucosa, leading to improved uptake of curcumin, as well as the other ingredients in our formula which have been clinically shown to have enhanced effectiveness when paired with piperine. Delivering 750mg of Longvida® Optimized Curcumin per serving, as well as 10 other clinically dosed nutraceuticals, we have formulated one of the most potent health supplements that cutting edge technology is able to offer.
References:
Carotenoids are known to have benefits in human health for their health benefits to reduce disease – particularly eye diseases and certain cancers1. Some common carotenoids are beta-carotene, lycopene, and lutein. Carotenoids are comprised of two different types: xanthophyll or carotenes, which cannot be synthesized by humans and must come from diet from algae, plants, and fungi2. Carotenes do not possess an oxygen molecule, while xanthophylls possess one or several oxygen atoms in their molecular structure in the form of a hydroxyl (-OH) or ketone (=O) group. The difference between Carotenes and Xanthophylls can be seen in the figure below comparing beta-carotene (a carotene) with cryptoxanthin (a xanthophyll). Note that the only difference between these two structures are an oxygen atom in the form of a hydroxl (-OH) group.
Figure 1: The structural difference between Beta-Carotene (Carotene) and Cryptoxanthin (Xanthophyll) differs only by a hydroxyl (-OH) group.
Due to the many conjugated double bonds in each type of carotenoid, these compounds are very colorful: with carotene compounds generally being orange, and xanthophyll compounds generally being yellow. These conjugated double bonds are also the reason for the antioxidant properties of all carotenoids. Astaxanthin is unique in the class of xanthophylls because it contains both hydroxyl and ketone functional groups at each end of the structure.
Figure 2: The Structure of Astaxanthin
This makes astaxanthin lipophilic (fat soluble) in the center and hydrophilic (water soluble) at each end of the structure. This unique structure allows astaxanthin to position itself across a cell membrane, linking cell membrane from inside to outside. This superior positioning of astaxanthin results in better biological activity compared to other common antioxidants (such as vitamin c and beta-carotene)3.
Figure 3: Astaxanthin positions itself across a cell membrane, protecting the cell from the inside and outside
Since carotenoids are fat soluble, they are transported via the lympathic system into the liver. Due to this, carotenoids like astaxanthin are better absorbed when they are taken with a dietary fat source. After ingestion, astaxanthin mixes with bile acid and absorbed by intestinal mucosal cells. Astaxanthin is then assimilated with lipoproteins and transported into the tissues. Astaxanthin is considered one of the best carotenoids being able to protect cells, lipids, and membrane lipoproteins against oxidative damage4.
In terms of antioxidant protection, astaxanthin has proven itself to be the best; having been found to be 6000 times stronger than vitamin c, 800 times stronger than CoQ10, 550 times stronger than green tea catechins, and 75 times stronger than alpha-lipoic acid when it comes to singlet-oxygen quenching5. As discussed earlier, these very strong antioxidant effects of Astaxanthin come from its many conjugated double bonds in its structure, its keto and alcohol groups at each end of the structure, and its ability to span a cell membrane in order to protect a cell membrane from the inside and outside of the cell.
Since oxidative stress and inflammation are common pathophysiological features of atherosclerotic cardiovascular disease, astaxanthin would sound like a reasonable candidate for therapeutic benefit in protecting the heart from cardiovascular disease. In clinical studies assessing astaxanthin’s effects for atherosclerotic treatment, no adverse effects were reported and a reduction in biomarkers of oxidative stress and inflammation were seen with astaxanthin administration6.
Studies in several species such as dog, rat, and rabbit have demonstrated that astaxanthin protects the myocardium when administered orally or intravenously7. It has also been shown that consumption of beta-carotene is associated with a reduction in cardiovascular disease8. Though the amount of current human studies showing the relation of astaxanthin with prevention in cardiovascular disease are not plentiful due to astaxanthin being a newly studied compound - with astaxanthin having much more pronounced antioxidant and anti-inflammatory effects than beta carotene, we can expect it to be more effective.
In humans, use of astaxanthin reduced LDL by inhibiting LDL oxidation with doses between 14-21mg/day with no other change in diet9. Astaxanthin has also been shown in humans to increase HDL in several studies10 as well as improving glucose metabolism and triglycerides. In one study, 61 subjects used doses of 6-18mg/day of astaxanthin for 12 weeks and saw a significant decease in triglycerides and a significant increase in HDL. Adinopectin, a protein hormone involved in regulating glucose levels, also showed significant increase in the groups using 12 and 18mg/day astaxanthin11. In addition, astaxanthin shows promise in reducing high blood pressure by modulating nitric oxide and relaxing the blood vessels12.
As interest in this compound continues to develop over the past few years, astaxanthin continues to be researched across different disease models. As an antioxidant, anti inflammatory, anti apoptic, and potential to promote or maintain neural plasticity, astaxanthin shows promise in exerting strong neuroprotective effects. Astaxanthin promotes activity of antioxidant enzymes, maintaining function of these enzymes has important contribution to normal aging, neurodegenerative diseases, and brain injury13.
In addition to increasing adinopectin levels, astaxanthin has been shown to reduce hyperglycemia-induced oxidative stress in pancreatic beta-cells and improve glucose and serum insulin levels16.
Astaxanthin’s antioxidant effect has also been shown to be beneficial in improved eye health, and treatment of retinal ischemia18 – a condition where blood flow is reduced to the eye.
Skin health declines over time due to UV damage, damage to DNA, reduced antioxidant production, inflammatory response, and collagen and elastin degredation. Again, here is where astaxanthin’s potent antioxidant and anti-inflammatory effects help to reduce skin damage, repair DNA, and enhance the immune system17.
Due to being a common additive in animal diets, nearly 95% of astaxanthin is mass produced synthetically for cost efficiency. However, the increased demand for human consumption is creating a need for more naturally produced astaxanthin, since synthetic astaxanthin has shown safety issues in humans14 and natural astaxanthin may be up to 3x more potent in antioxidant activity than synthetic15. Natural astaxanthin is produced from algae, yeast, and crustacean byproduct.
To summarize, astaxanthin is rather new to the world of dietary supplements, but has shown to be one of the strongest antioxidants available (6000x stronger than vitamin C) due to its unique structure and ability to position itself across the cell membrane in order to protect the cell. Astaxanthin also has documented human use showing its effectiveness at increasing HDL and adinopectin, while decreasing LDL and triglycerides. Astaxanthin has neuroprotective benefits as well as skin and eye benefits. Leviathan IRE, our complete health optimization supplement, features the high-end clinical dose of 18mg of natural astaxanthin produced from algae (Haematococcus pluvialis) per serving in order to fully gain these benefits.
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For drugs and supplements, there are several methods of administration. Oral administration (swallowing a pill, powder, etc) is the most used method for dietary supplements due to convenience, but also encounters the most issues when it comes to bioavailability. When a drug or supplement is consumed orally, it travels through the intestines, then to the portal vein, and then to the liver. Some metabolism occurs through enzymes in the intestines, but In the liver is where most metabolism occurs. After it is processed through the liver it will finally reach systemic circulation (becomes active). As said before, the amount of the drug or supplement that reaches systemic circulation is the amount of that compound which is really bioavailable.
In order to bypass the First Pass Effect, a method of administration must be used that will prevent the drug or supplement from going through the liver before undergoing systemic circulation. There are several ways this can be done:
The first and most obvious way to bypass the First Pass Effect from the liver is delivering the drug or supplement via Injection. A compound can be injected Intravenously (IV), Intramuscularly (IM) or Subcutaneously (SubQ). Intravenous Injection is the most superior form of injection where the compound immediately reaches systemic circulation and 100% of the compound is absorbed. In fact, bioavailability of any compound is defined as 100% if it is delivered by IV injection1. Intramuscular injections may be used where the compound is less water soluble, but absorption of IM injections can be slow, depend on the water solubility of the compound, dispersion of the solution and blood flow at the injected site. Due to this, in some cases oral administration can have better bioavailability than IM injection2. Subcutaneous Injections are used when the compound needs to be delivered more slowly than an IV Injection.
This way to bypass the First Pass Effect still involves taking the supplement orally. If the supplement is highly lipophilic, instead of going into the portal vein, these compounds can be absorbed in the intestinal lymphatic system. After being absorbed through the intestine, the lymphatic system then transports the compound into blood circulation, where it reaches systemic circulation. This method of delivery is very popular because of its ease of use, and relative ease to apply increased lipophilicity to many compounds. For this reason, creating liposomal supplements is an effective way to increase the lipid solubility of the compound, and will allow it to be absorbed through the lymphatic system. Again, doing this allows the supplement to bypass the liver, and can drastically increase bioavailability of previously poorly-bioavailable compounds5.
In some cases, a compound should not bypass First Pass metabolism, and therefore should be taken orally, such as in the case of prodrugs. When prodrugs are taken, they are in an inactive form, they are then converted into their active form when they are metabolized in the liver. Therefore, doing an IV Injection of a prodrug will result in zero active compound rather than 100%, because first pass metabolism is required to convert the compound into its active and usable form.
Before going systemic, drugs or supplements get metabolized. The metabolizing process is broken into 3 phases: Phase I, Phase II, and Phase III6.
Phase I Metabolism is where a class of oxidase enzymes, known as the Cytochrome P450 (CYP450) enzymes undergo reactions with the drug or supplement that add oxygen to the molecule in the form of a carboxyl (=O) or hydroxyl (-OH) group. (figure phase I). The purpose of these reactions from the CYP450 family is to make the drug more water soluble, so it can be excreted from the body through the kidneys. Drugs or supplements that are more water soluble are easier eliminated from the body.
Figure 2: Examples of CYP450 Reactions Occurring in Phase I Metabolism which increase the water solubility of the molecule.
The two most common enzymes of the CYP450 family are CYP3A4 and CYP2D6. With CYP3A4 being responsible for metabolizing over 50% of drugs, while CYP2D6 can vary in effectiveness per person, which results in some people who are able to metabolize drugs quicker or more slowly than others7.
Some substances are known to inhibit activity of CYP3A4, thus increasing the bioavailability of some compounds. One potent CYP3A4 inhibitor is 6,7-dihydroxybergamottin, which is the compound responsible for ‘the grapefruit effect.’ This compound is able to enhance the effects of many supplements, as well as anabolic steroids which are taken orally because they reduce the effect of liver metabolism action via the Phase I metabolism10.
In Phase II metabolism, enzymes called transferases; primarily UDP-glucuronosyltransferases (UGTs), transfer more polar molecules onto the drug in order to make it more water soluble. This process is also used to detoxify drugs which may otherwise be toxic, such as acetaminophen. These reactions are called conjugation reactions, and involve the transfer of an acetyl, sulfate, or glucuronate group to the drug or supplement8. An example of this Phase II metabolism on a supplement can be seen with curcumin, where curcumin undergoes the addition of a sulfate (sulfation) or glucuronate (glucuronidation) group.
This process converts curcumin to an inactive form, where it is then eliminated through the kidneys as waste. This process is the reason why curcumin has poor bioavailability.
Phase III metabolism involves further metabolizing of some compounds, though most do not need to undergo this process. Phase III is primarily responsible for moving metabolites and conjugates to excretion, where a gene family known as the transport system such as P-glycoprotein remove Phase II products from to the extracellular medium, where they are excreted from the body9.
To summarize, the effect of supplements completely relies on the bioavailability of that supplement. In order for a supplement to become active, it must reach systemic circulation. Experiments that take place outside of the body may not reflect the same effects that happen inside of the body due to bioavailability. A supplement that is taken intravenously will have 100% bioavailability. Consuming a supplement orally means it is metabolized in the liver, where It is subject to Phase I and Phase II Metabolism and converted to non-beneficial metabolites which are excreted from the body through the kidneys. Supplements with poor bioavailability (such as Quercetin and Curcumin) can still have their full effects in the intestines, since they are not yet metabolized in the liver. So, if using supplements for their benefits in the intestine, there is no need to be concerned about bioavailability. Taking a supplement sublingually or enhancing its fat-soluble properties, so it is absorbed through the lymphatic system are ways to bypass liver metabolism and drastically increase the bioavailability of a supplement which has poor bioavailability.
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DISCLAIMER: These statements have not been evaluated by the Food and Drug Administration, these products are not intended to diagnose, treat, cure, or prevent any disease.
To understand TUDCA and its properties, it is first important to understand the larger class of compounds it belongs to: The Bile Acids. Bile Acids are synthesized from Cholesterol in the liver via cytochrome P450, a system of enzymes responsible for drug metabolism. From Cholesterol two Bile acids are made: Cholic Acid and Chenodeoxycholic Acid1. These are known as the primary bile acids.
Figure 1: The Two Primary Bile Acids
From the primary bile acids, bacterial metabolism which results in the reduction of the alpha hydroxyl group at carbon position 7 is how the secondary bile acids: Deoxycholic and Lithocholic acid are made.
Ursodeoxycholic Acid (UDCA) is synthesized when deoxycholic acid undergoes reduction of its hydroxyl group on carbon position 12 and the addition of a 7-beta hydroxyl group. Compared to its parent primary acid cholic acid, UDCA has its hydroxyl groups on opposite sides of the three-dimensional molecular structure.
This could be a reason for some of its unique effects. From here, UDCA can be conjugated with either glycine or taurine to give either Glycoursodeoxycholic acid or Tauroursodeoxycholic Acid (TUDCA).
It is important to note that all bile acids, primary or secondary, can be conjugated with an amino acid: Taurine or glycine to form a bile salt. The addition of the amino acid makes the bile salt more water soluble. Bile salts are amphipathic, meaning they are both water and fat soluble. This property allows them to emulsify lipids and digest fats. Bile salts are responsible for digesting fats as well as fat soluble vitamins, while bile acids are unable to digest fats1.
Bile Acid production from Cholesterol is the bodies’ primary pathway for maintaining healthy cholesterol levels. About half of the total cholesterol in the body is used to make bile acids2. Bile salts inhibit cholesterol 7alpha-hydroxylase, the enzyme responsible for producing bile acids from cholesterol. This enzyme inhibition decreases production of bile acid. Due to being potentially toxic to cells, the concentrations of bile acids are tightly regulated3.
While amphipathic bile acids like TUDCA have beneficial properties in the liver, buildup of the bile acids chenodeoxycholic acid or deoxycholic acid or their glycine or taurine conjugates have toxic effects on the liver.
A buildup of too many lipophilic bile acids in the liver such as Chenodeoxycholic acid or deoxycholic acid can cause toxic effects like cell death, leading to cholestasis. Since TUDCA is amphipathic, it is able to antagonistically compete with these harmful bile acids in the liver, displacing them from the liver, lowering their concentration and harmful effects.
TUDCA is incredibly potent at reducing liver enzymes, where one study showed a reduction of liver enzymes by 51% over a two month period at 750mg/day4.
In addition to reducing liver enzyme levels, TUDCA has been shown to stimulate hepatocyte proliferation (Growth of new liver cells) in humans at doses as low as 10-13mg/day for 3 months5.
TUDCA has also been shown to be effective at treating chronic hepatitis (Liver inflammation that has occurred for 6+ months) in doses of 500-750mg/day6.
TUDCA is a candidate drug in the treatment of Non Alcoholic Fatty Liver Disease (NAFLD) and has been shown to reduce progression of NAFLD by reducing gut inflammation, improving intestinal barrier function, decrease intestinal fat transport, and controlling gut flora in the intestine7.
Although UDCA is also an amphipathic bile acid used to treat cholestasis, TUDCA has superior bioavailability and absorption due to the attached taurine molecule. In one study comparing the effects of TUDCA vs UDCA for treatment of biliary cirrhosis (An autoimmune disease which destroys the bile ducts) patients were given either TUDCA or UDCA at 750mg/day for 2 months. Enrichment by Ursodeoxycholic acid was significantly higher in the group given TUDCA than the group given UDCA itself. The group given UDCA also had higher lithocholic acid levels (A toxic bile acid) than the TUDCA group. Bile excretion was measured at 8% for the TUDCA group vs 23% for the UDCA group, meaning more TUDCA was absorbed and retained vs UDCA. This study shows concrete evidence that TUDCA is more effective than UDCA in real human studies4.
TUDCA has been shown as an effective treatment for damaged and inflamed kidneys caused by high salt intake by decreasing renal cell death and inflammation8.
In addition, TUDCA treats acute kidney injury caused by reduced blood flow to the kidney by inhibiting endoplasmic reticulum stress. This is caused by TUDCA increasing the protein folding ability in the Endoplasmic Reticulum, which results in reduction of the death of cells by protein unfolding9.
Due to the ability for Bile acids to cross the blood brain barrier (BBB), TUDCA has a direct neuroprotective effect and possibly an indirect neuroprotective effect by inhibiting glia and endothelium activation, reducing neuro-inflammation10.
TUDCA has been shown to reduce apoptosis (cell death) in the heart following myocardial infarction (heart attack), showing its potential for treatment of acute myocardial infarction11.
Studies have demonstrated that Endoplasmic Reticulum (ER) stress contributes to insulin resistance. In one study, 20 subjects were given 1750mg TUDCA/day for 4 weeks. By the end of the study, liver and muscle insulin sensitivity had increased by 30%. Muscle insulin signaling was also increased in the group given TUDCA compared to the control group13.
Bear bile such as TUDCA has been used in Chinese medicine for thousands of years, mostly for liver diseases and eye health. TUDCA has been shown to slow retinal degeneration, and preserve the function of rods and cones12.
As can be seen from most of the benefits of TUDCA that have been listed here, these benefits are due largely in part by the ability of TUDCA to reduce Endoplasmic Reticulum (ER) Stress and reduce the levels of misfolded proteins. Misfolded proteins can lead to many neurodegenerative diseases, and ER stress is involved in aging, inflammation, diabetes, neurodegenerative diseases, and cardiovascular diseases14. TUDCA is a known ‘chemical chaperone’ – a class of molecules which function to enhance the folding or stability of proteins. TUDCA’s ability as a chemical chaperone has also shown promise in alleviating different forms of colitis, suggesting potential treatment for inflammatory bowel diseases15. Compared to another chemical chaperone, TUDCA showed better cell viability and decreased cell apoptosis (cell death), showing a superior ability to protect cells16.
Compared to many supplements, TUDCA is highly bioavailable and does not have issues with being properly absorbed. Indeed, TUDCA is better absorbed than its prescription drug counterpart UDCA, where bile excretion in patients given 750mg TUDCA/day was only 8% compared to those given the same amount of UDCA was 23%4.
Hydrophilic Bile acids such as TUDCA induce CYP3A, a major drug metabolizing enzyme, while toxic bile acids such as chenodeoxycholic acid and deoxycholic acid show inhibition of CYP3A17. The enzyme metabolizing properties of CYP3A are important to understand, as some drugs and supplements are CYP3A inducers, while others are CYP3A inhibitors. It Is a common practice in supplements to combine products with the ingredient Piperine, which is a CYP3A inhibitor that is known to increase the bioavailability of other CYP3A inhibiting supplements such as Curcumin18, Quercetin19, and Resveratrol20. Due to the fact that TUDCA is a CYP3A inducer while more toxic bile acids are CYP3A inhibitors, combining piperine with TUDCA may decrease the bioavailability of TUDCA due to competing drug metabolism interactions17.
To conclude, TUDCA is the taurine conjugated bile salt of the bile acid UDCA, with unique properties, mainly in reducing ER stress by protein unfolding due to its 7-beta hydroxyl group and increased hydrophilic properties. TUDCA is able to compete with water insoluble toxic bile acids in the liver to eliminate them from the liver, resulting in a decrease of liver enzymes and alleviation of problematic issues. Doses as low as 10-13mg/day of TUDCA have been linked with a decrease in liver enzymes5, while doses up to 1500mg/day for 6 months have been given with no side effects21. With doses of 500mg, 1000mg, and 1500mg/day given in patients with biliary cirrhosis, the group given 1500mg/day saw the most beneficial results, while all doses were considered effective22.
At Leviathan Nutrition, our TUDCA is routinely check for quality (Lab results here: https://leviathan-nutrition.com/pages/testing-results) to ensure a high quality product. Readers of this blog can use the discount: 'TUDCA' to receive 10% off of our TUDCA: https://leviathan-nutrition.com/products/leviathan-nutrition-tudca
References:
DISCLAIMER: These statements have not been evaluated by the Food and Drug Administration, these products are not intended to diagnose, treat, cure, or prevent any disease.
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Berberine is a quarternary ammonium salt (Figure 1) found in the roots, rhizomes, stems, and bark of plants such as Barberry (Berberis Vulgaris), Tree Turmeric (Berberis Aristata), Goldenseal (Hydrastis canadensis), and Oregon Grape (Mahonia Aquifolium). The use of berberine plant rich species such as the Berberis family has been used in Asia for over 3000 years1. Many clinical and experimental studies show that berberine has pharmacological properties such as immunomodulatory, antioxidative, cardioprotective, hepatoprotective, and renoprotective effects. In medicinal chemistry, the structure of Berberine has been modified to create bioactive derivatives in order to increase potency and selectivity2.
Figure 1: The Structure of Berberine
Berberine has been used successfully in the treatment of type 2 diabetic patients, and had similar hypoglycemic effects as the prescription diabetic drug metformin. In a 3 month trial, patients taking 500mg Berberine 3x daily saw decreases in Hemoglobin A1c, blood glucose levels, triglycerides, as well as total and LDL Cholesterol 3. In the second part of the study, subjects also experienced plasma insulin reduction of up to 44% 3.
Another study with 116 patients with type 2 diabetes and dyslipidemia were given 1g of berberine per day for 3 months. These subjects experienced a significant decrease in plasma glucose levels, triglycerides, and LDL cholesterol compared to the placebo group. Patients given the berberine also experienced an increase in Glucose Disposal Rate (Greater Insulin Senstivity)4.
The results of these studies are extremely beneficial due to the limited availability of effective medications for blood glucose. Single berberine is a single, purified compound found in several plant sources, it has the potential to be effective for reducing blood glucose levels in populations worldwide.
Berberine is able to improve glucose metabolism and thus insulin sensitivity by activating AMPK – an enzyme responsible for glucose uptake – as well as induction of glycolysis13.
In addition to being used for effective hypoglycemic treatment and increasing insulin sensitivity, Berberine is effective at improving cholesterol levels, as the studies mentioned above also showed with decreased LDL Cholesterol levels. In a separate study, using Berberine for 3 months reduced serum cholesterol by 29%, LDL cholesterol by 25%, and triglycerides by 35%. Berberine lowers cholesterol by acting upon the Low Density Lipoprotein Receptor (LDLR): Elevating LDLR expression by stabilizing the mRNA. This means that Berberine is capable of lowering cholesterol through a different mechanism than statin drugs5.
Berberine also possesses anti-inflammatory and anti-tumor effects. Berberine’s anti-inflammatory activity comes from inhibiting mitogen-activated protein kinase and cellular reactive oxygen species production6. Berberine also inhibits gene transcription by forming strong complexes with DNA or RNA to induce DNA damage and telomerase inhibition7. These effects of berberine may lead to cell death in carcinogenic tumors. Use of Berberine with radiation therapy enhances the cytotoxic effect on tumors and reduces side effects from the therapy8.
Making modifications to the chemical structure of Berberine is able to increase its bioactivity, bioavailability, and specific effects of the molecule (Figure 2).
Figure 2: Modifications at Numbered Positions Change the Properties of Berberine.
Adding functional groups at carbon 8 or 13 will increase the antimicrobial activity of berberine. Adding a substituent at carbon position 9 will enhance its anti-tumor activity9.
Berberine also shows promise in the treatment of Non Alcoholic Fatty Liver Disease (NAFLD) Treatment. Patients who received 500mg of Berberine 2x per day for 16 weeks saw reduced bodyweight, an improvement in lipid profile, and a significant reduction of Hepatic Fat Content. Berberine shows promise in regulating hepatic lipid metabolism10.
Because Berberine has relatively poor bioavailability, much of its activity occurs in the gastrointestinal system. For this reason, it is an effective treatment for Inflammatory Bowel Disease and possesses strong anti-inflammatory effects on the digestive system11.
Berberine has well established anti-microbial properties and can control infection by bacteria, viruses, fungi, protozoans, and helminthes. An example of this is Berberine has the ability to inhibit E.Coli12. Berberine is sold as an over the counter drug for gastrointestinal infections in China.
Berberine has many uses, ranging from use in reducing blood glucose levels and increasing insulin sensitivity, improving cholesterol levels and triglycerides, anti-inflammatory and gastrointestinal benefits. These benefits can be very useful for bodybuilders or other athletes, with 500mg given twice daily proving to be a beneficial dose in clinical studies. Our new upcoming product, Leviathan Nutrition Ire will feature 1000mg of Berberine per serving, providing all of the benefits mentioned in this article.
References:
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111450/
DISCLAIMER: These statements have not been evaluated by the Food and Drug Administration, these products are not intended to diagnose, treat, cure, or prevent any disease.
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Chromium supplementation has been found to further reduce fat and spare muscle when following an exercise and diet regimen compared to placebo2. Chromium is also useful for improving brain function, lowering cholesterol, improving immune system function, and improving diabetes symptoms.
In the human body, Chromium is used to synthesize a complex known as Glucose Tolerance Factor (GTF): The biologically active form of trivalent Chromium. GTF physiologically enhances insulin activity by binding to insulin, binding to the cell and is able to potentiate its action by three-fold3, and when exogenous GTF is administered alongside insulin, GTF and insulin act synergistically4.
The molecular structure of GTF is not yet completely known, but has been proposed to be a complex of chromium, nicotinic acid (vitamin B3), and a few amino acids such as glycine, cysteine, and glutamic acid5.
Though all trivalent Chromium sources lead to synthesis of GTF, not all chromium sources are created equal. Dietary Chromium GTF – where trivalent chromium is bound in a matrix of Saccharomyces Cerevisiae (Brewer’s Yeast) Nutritional Yeast is the most effective at reducing insulin resistance and performs best compared to other Chromium sources6. This is because consumption of GTF does not get degraded when ingested, resulting in more available GTF in the body. Chromium GTF is also necessary for the elderly and insulin-requiring diabetics, because they have difficulties converting Chromium to GTF on their own7.
When choosing a supplement for chromium GTF, it is important that the ingredients show chromium bound to Brewer’s Yeast/ Saccharomyces Cerevisiae, as labels are able to state they contain chromium GTF due to its biological activity of forming GTF after ingestion, but these products do not contain the chemical structure of GTF, which is necessary for optimal effects of Chromium.
References:
1. https://www.ncbi.nlm.nih.gov/pubmed/25231674
DISCLAIMER: These statements have not been evaluated by the Food and Drug Administration, these products are not intended to diagnose, treat, cure, or prevent any disease.
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