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Introduction

In this article I would like to discuss the nutrients necessary for the liver to carry out one of its main functions, Detoxification.  


Detox function of the liver

 

The marvel of the way the body functions, the liver is no exception, especially when considering the detox function which is performed by sophisticated mechanisms within the liver cells.  The reason why we need a detox mechanism in the first place is that many toxins that enter the liver are fat soluble( non polar) which cannot be just excreted by the body using the urinary tract or bile as they could be, if they were water soluble (polar).  In essence the detox function is simply to convert lipid(fat) soluble toxins into water soluble toxins so they are easily eliminated from the body via the urinary tract or the bile channel. In fact fat soluble toxins will attach themselves to fat adipose tissue and can stay there for years if they are not released from their ‘captor’ through weight loss for example.

The liver achieves its detox function in 3 stages ( Stage 0 involves the GI Tract), stage 1 converts the toxin into something less harmful and stage 2 converts the converted intermediary into a water soluble substance. Stage 1 uses a family of enzymes called cytochrome P450 Enzymes (CYP450)* that are involved in steroidogenesis which means they are used to synthesize steroid hormones like testosterone, estrogen etc and drug catabolism (breaking down molecules). In the liver specifically, these enzymes are referred to as microsomal which is a fragment of the endoplasmic reticulum part of a cell ( outside of the nucleus ) because that’s where they are located and end up in the cell membrane where they go to work on stage 1 detox.

* There are 50 or so CYP450 enzymes, 6 of which are responsible for metabolising 90% of ingested drugs. Adverse effects caused by pharmaceuticals are a result of the multiple inhibition/induction of these enzymes being used to expel what the body considers a toxin or poison i.e pharmaceutical drugs.  The problem with taking drugs, their associated adverse effects is exponentially accentuated by the potentiation of taking multiple drugs; who knows what disastrous effects are being unleashed against the liver metabolism process. This is a quote from the website: ‘American Family Physician’:

Many drug interactions are the result of an alteration of CYP450 metabolism

This is why there are many cases of death from prescription drugs, but many physicians are unaware of the risks, or chose to ignore them.

Liver detox required nutrients

If you scan the web you will find various detox regimes, but if you have an ideal dietary lifestyle including adequate exercise, eating organic fruits, veg, seeds nuts and grains and supplementing with the 90 essential nutrients from a whole food source daily there is no need for these liver detox regimes, because the liver is doing it automatically.  I don’t believe science knows specifically what nutrients are used, since they are busy studying new ways to alter the body’s physiology, but we have a general idea. Interestingly, important nutrients required by the liver to detox contaminants are proteins and water, since the former provide amino acids and enzymes, while the latter provides oxygen,hydrogen and hydroxyl groups as well as a degradation medium for toxic agents.  The detox enzymes require cofactors for activation provided by vitamins and minerals. This two stage process also require a means to quench the oxidation that occurs by the use of antioxidants. Stage 1 detox occurs in the cell membrane, while Stage 2 occurs in the cytosol (the fluid portion of the cytoplasm) Before xenobiotics like toxins, pharmaceutical drugs, alcohol are transported to the liver, they are faced with the gastrointestinal tract.

Initial stage detox The Gastrointestinal tract

A high concentration of Cyp3A4 detox enzyme has been found at the tip of the villi in the small intestine.  This cytochrome P450 ( type 3A4) oxidises small particle drugs and toxins so they can be excreted from the body. Some drugs are induced by these enzymes and some are inhibited. Drugs such as Amitriptyline ( prescribed for depression and other cognitive dysfunction), Carbamazepine ( anticonvulsant, and antiepileptic drug),  Clarithromycin (antibiotic), Cyclosporine ( immunosuppression), Lignocaine ( to numb tissue), Midazolam ( sedative ) and others are metabolised by the Cyp3A4 enzyme meaning inducement. Whereas drugs such as Troleandomycin ( antibiotic), Ketoconazole ( an antifungal medicine ) and Gestodene ( a synthetic progestogen ) are known to inhibit this enzyme. What appears to happen in this intestinal first pass detox activity is ‘antiporter’ activity of the CYP enzyme which means that there is a mechanism to export xenobiotics out of the cells and into the intestinal lumen preventing toxin accumulation at the intestinal barrier. Basically, antiporting is a way of transportation reversal ( “send it back from where it came, until we can deal with it”), and acting as a buffer for the liver. Two genes have been identified for this purpose MDR1 and MDR2 (Multidrug resistance ) which inhibit drug action ( because the body does not want this poison invading its space ). The gut flora also affect detoxification, where pathogenic overgrowth can add to the toxic load, and what makes the situation worse is that in some circumstances some gut colonies can remove conjugation (stage 2 detox) reproducing the original xenobiotic by a process called ‘enterohepatic recirculation’, also increasing toxic load, so its important to have good gut balance. This arrangement is shown in the diagram below where the CYP450 ( 3A4) enzymes oxidise some toxins as a first pass ( Red stars ) and sent to the liver via the portal vein, while the antiporter activity of the enzyme sends back some toxins (Black stars) to prevent a toxin buildup and thus acts as a buffer for the liver to prevent it from being overwhelmed.

First stage liver detox

From studies that date back over 100 years the quest to understand how the liver detoxes so many different toxic substances uncovered the sheer complexity of this task. Ten families of stage 1 enzymes including 35 various genes.  Multiple chemical reactions are required, including oxidation*, reduction*, hydrolysis ( adding water for a biological reaction), hydration ( water intake) and Dehalogenation ( downgrades toxic chemicals specifically organohalides used in pesticides). Mineral and vitamins are required as cofactors for enzymatic action. The P450 enzyme typically uses oxygen and NADH*(Nicotinamide Adenine Dinucleotide)  as a cofactor. As a consequence, the outcome of the detox phase/stage 1, in some cases, can potentially produce a more toxic substance compared to the original toxin or xenobiotic.

*If you have read previous articles in this series NADH is a coenzyme found in all living cells and when used in metabolism this molecule is involved in redox (oxidation/reduction) reactions where  NAD is an oxidising agent that produces a reducing agent NADH that can donate electrons. NADH is able to conduct electron transfer as in this case detoxification.

Nutrients used in the first stage liver detox

Minerals like Zinc is needed to activate alcohol dehydrogenase, the enzyme required to transform hydroxylated toxins from their alcohol form into an aldehyde form using coenzyme NAD. The following process to convert aldehydes which are more toxic than its alcohol derivative into a water soluble acid form requires Molybdenum to activate the enzyme aldehyde oxidase. This sub process is also used to convert vinyl chloride ( inhaled particles from working with PVC ), Formaldehyde ( which is actually metabolised rapidly into formic acid( ants spray this substance on predators that invade the nest ) to avoid accumulation in the body), other industrial chemicals and exhaust fumes. Copper and Magnesium are required for other CYP enzymes while Iron is needed for the enzyme alcohol dehydrogenase for hydroxylation and dehalogenation reduction. Since this detox step takes place within the cellular membrane, a source of choline from the diet (egg yolk for example) is required to assist the body in synthesizing phosphatidylcholines, a major constituent of membranes. Vitamins B1,B2, B3 are also used as co-factors. Because oxygen is involved in the detox process many free radicals are produced, so antioxidants are used to quench this oxidative deluge which include Glutathione, Vitamin A (Carotene), Vitamin C, Vitamin E ( Tocopherol), Coenzyme Q10, Folic acid, and Thiols ( sulphur compounds) from Garlic and cruciferous vegetables, as well as a source of a phytochemical Limonene ( citrus fruits like lemons ( zest especially), oranges, tangerines, black pepper, celery, dill, fennel, caraway),  which also stimulate the detox process. In addition the 3 branched chain amino acids ( BCAA ) leucine, Isoleucine and Valine (3 of the 12 essential amino acids) are required to stimulate protein synthesis from various gene expression associated with the detox process.

Nutrients used in the second stage liver detox

Although the Intermediary metabolites produced from the first detox stage are less lipid soluble, further processing is required to make them fully water soluble so they can be excreted out of the body.  This second stage (Phase 2) detox performs additional chemical reactions that include Sulfation, Glucuronidation, Glutathione conjugation, Acetylation, amino acid conjugation and Methylation. This second stage is referred to as the conjugation pathway, where the liver cells add another substance to stage 1 to achieve water solubility. Nutrients required to perform these reactions are amino acids Glycine, Taurine ( essential), Glutamine and N-acetylcysteine, cysteine and Methionine.   N-acetylcysteine (NAC) is a man made modified form of L-cysteine. NAC can be purchased as a supplement.  L-Cysteine is synthesized in the body, but it can also be provided in the diet from high protein foods such as meats ( chicken, pork, turkey, duck), cheese, yoghurt, eggs, sunflower seeds, legumes and oat bran. The body synthesizes L-cysteine from serine (contained in high protein foods as well, such as dairy and meats), and methionine ( essential amino acid contained in high protein foods such as dairy, meats, eggs and nuts) using folate, vitamin B6 and B12 as cofactors (these can all be sourced from beans (chickpeas,pinto beans), lentils, spinach, avocado, bananas, wild salmon, tuna and liver). There are other health benefits from L-cysteine such as an expectorant to break up mucus and the man made version is given to treat acetaminophen overdose working as a drug detoxifier. Acetaminophen or Tylenol described by Dr Bergman as one of the most destructive drugs on the market if taken in excess can deplete liver cells of glutathione causing liver cell damage.  Unless you have overdosed on Tylenol, I am not sure if it is necessary to take a NAC supplement, since the body produces L-Cysteine. Glycine rich foods include high protein foods such as fish,meat,dairy, spinach, kale, cauliflower,cabbage,pumpkin,banana,kiwi, cucumber and beans. Taurine rich foods include shellfish like scallops, clams, mussels, and the dark meat of turkey and chicken and small amounts are contained in dairy products.

Other Nutrient considerations

Milk Thistle, a very interesting herbal medicine is the liver’s best friend,since its flavonoids called Silymarin supports the liver detox capability by preventing glutathione depletion in the liver cells and increases glutathione status within the liver. In addition, it stabilises the liver cell membrane by altering the structure to prevent the ingress of toxins. New liver cell regeneration is also stimulated by milk thistle as well as preventing the recirculation of toxins and damaged liver cells.  Turmeric that contains Curcumin is infamous for its anticarcinogenic and antioxidant properties, also enhances glutathione, providing additional benefit toward liver detox. Green tea contains a powerful yet poorly absorbed polyphenol, catechin, called Epigallocatechin gallate (EGCG) which acts as a antioxidant. Trace amounts of this substance are also found in apple skin, plums,onions, hazelnuts, pecans and carob powder ( Cocoa ). Catechins are a natural phenol and antioxidant and a plant secondary metabolite that are part of the flavonoid family. Some research claim that cocoa contains one of  the highest amounts of catechin measured 108 mg/100g. Prune juice is also rich in this phenol as well as Acai fruit ( acai powder is a health supplement ) and peaches.

The Glucuronidation pathway

As mentioned above, one of the chemical reactions within the Stage 2 liver detox processes is glucuronidation ( called conjugation in which a toxin is packaged into a water soluble compound known as a ‘Glucuronides’) where glucuronic acid, a derivative of glucose, and highly soluble, is produced in the liver to bind to substances such as ‘used’ steroid hormones, polycyclic aromatic hydrocarbons as in wood burning, nitrosamines from cured meats, fungal toxins and used endocrine hormones such as estrogen. There is another issue with respect to a bacterial enzyme Beta-glucuronidase, produced by anaerobic intestinal bacteria to break down complex carbohydrates like grains, beans, rice,fruits and vegetables. Beta-glucuronidase is involved in nutrient separation or deconjugated, extracting the aglycone portion from natural plant substances such as lignans and flavonoids. If the gut becomes dysbiotic from poor dietary choices then the level of this enzyme elevates, causing the undoing of the packaged toxin conjugation, releasing the toxin to be reabsorbed into the bloodstream and then adding to the liver’s toxic load. Natural substances such as apples, grapefruit ,broccoli, brusselsprouts. cabbage, legumes, cucumber, pears, peaches, apricots, cherries, plums, almonds, strawberries, raspberries, blackberries, watermelon, oranges, lemons and limes, all contain a substance called Calcium D-Glucarate,  which is known to inhibit the level of this enzyme. Garlic is known to stimulate the liver’s detox processes, and there are probably others, but if you are supplementing the 90 essential nutrients and consuming hearty portions of life giving fruits and vegetables, nuts, and seeds I would say you probably have the ‘biological arsenal’ necessary to keep your body free of toxins.

Detox anomalies

Biphasic response in terms of detox nutrients specify that a low dose of a nutrient stimulates the detox process and other nutrients inhibit certain enzymes and pathways, meaning that the amounts found in food stimulate the detox processes, but the amounts found in isolated synthetic nutrients possibly inhibit. This makes sense because of natures balance in natural plant based food. Outside of the natural detox process of the liver, most detox regimes include fasting, but if you are unhealthy and nutrient deficient and begin fasting it is quite likely that it will liberate toxins that are stored in the adipose tissue which will make your situation worse.  These apply to the fat soluble toxins, but the water soluble toxins that are already in the form for excretion, must be excreted and instead of relying on the urinary or fecal pathway for toxin elimination go out and sweat them out…Why ?, because the toxins are guaranteed to exit your body. Depending on the PH of the urine this determines if the toxin gets excreted or reabsorbed, so an acidic PH urine will tend to reabsorb the toxin, and excessive amounts of reabsorbed toxins could be potentially carcinogenic.

Something else to consider, to support the livers detox protocol, is supplying the body with binders for the toxins, and plant fiber is one, so be sure to make and take smoothies every day as opposed to juices.  Some studies associate inhibition and stimulation with certain nutrients depending on where the P450 enzymes are located, because the same P450 enzymes that the body uses for detox purposes in the liver, also exist in the kidneys, and the enterocyte gut cells, but again the body’s innate intelligence will establish balance within the non nutrient deficient individual.

“Who are we without our addictions; without our media-induced hungers? So often the voices we hear echoing in our mind are not our own but that of our influencers. Isolation, while arguably going against human nature, is essential for mental and emotional health. Solitude is a detoxification of all that distorts our personality and misguides our path in life. It allows us to filter out the foreign opinions and hear our own voice—reach our authentic character—and practice fidelity to self.”

L.M. Browning, Seasons of Contemplation: A Book of Midnight Meditations


Check out the Previous Article in this series:

Nutrients in Food and their bodily purpose I (Phenols)

Nutrients in Food and their bodily purpose II (Lignans, Triterpenes, Phytosterols, Carotenoids and Fats)

Nutrients in Food and their bodily purpose III (Phenolic acids, sulphur,sulphides,sulphoxides )

Nutrients in Food and their bodily purpose IV (Glucosinolates, Sulforaphane, Indole-3-Carbinol)

Nutrients in Food and their bodily purpose V (Lipid distribution, absorbed fats, Criciferous Veg)


References/Acknowledgments :

  1. The effects of Cytochrome P450 Metabolism on drug response, interaction, and adverse effects American Family Physician Tom Lynch 2007
  2. Steroidogenesis Vivo Pathophysiology Richard Bowen
  3. Detox nutrients Healthknot.com
  4. What is L-Cysteine? Dr Axe
  5. The Detoxification enzyme system DeAnn Liska 1998
  6. What foods provide Calcium D Glucarate Jaime Harder Caldwell Livestrong 2017
  7. Maintaining a proper balance of Beta Glucuronidase for disease and cancer prevention Bio Foundations
  8. Epigallocatechin gallate, NAC, Trimethylglycine, Limonene, Phosphatidylcholine Wikipedia
  9. Seasons of Contemplation L.M Browning Goodreads quote

Author : Eric Malouin

 

 

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