Metabolic Enzymatic Detoxification Pathways

In this Page, I will first introduce the subject (Section A) and thereafter, go into toxicity exposure (Section B) and follow-up with an overview of the body’s detox system (Section C) and then conclude with an analysis of the three different metabolic detox phases (Section D). For detox enhancement techniques, see this other Page-document.

Section A

Introduction

Detoxification (“detox”) has been used to describe practices and protocols that embrace both complementary (fasting, colonic cleaning and more) and conventional (chelation or antitoxin therapy) schools of medical thought, as well as some that push the boundaries of scientific plausibility (such as foot pad and ionic foot detoxification).

In the context of human biochemistry, detoxification has been described as a specific metabolic pathway, active throughout the human body, that processes unwanted chemicals for elimination. This metabolic pathway involves a series of enzymatic reactions that neutralize and solubilize toxins, and thereafter, transport them to secretory organs (ie, the liver or kidneys), so that they can be excreted from the body. This type of detoxification is sometimes called xenobiotic metabolism, because it is the primary mechanism for ridding the body of xenobiotics (foreign chemicals). There is also another type of detox system called endobiotics (endogenously-produced chemicals).

Excess hormones, vitamins, inflammatory molecules, and signaling compounds, amongst others, are typically eliminated from the body by the same enzymatic detoxification systems that protect the body from environmental toxins, or clear prescription drugs from circulation. Metabolic detoxification reactions, therefore, are not only important for protection from the environment, but central to homeostatic balance of the body.

Section B

Poisons: Bio-toxins, Micro-toxins and Chemo-Toxicant Exposure

Toxins are poisonous compounds. This notion is usually pertains to toxins from living organisms. The term “bio-toxin” is used to emphasize the biological origin of these compounds. Man-made chemical compounds with toxic potential are usually called toxicants. The H.M. Institute prefers to concept of chemo-toxicants.  But the mainstream central distinction is between toxins of biological orgin and toxicants of synthetic origin. Both these poisons can exert their detrimental effects on health in a number of ways. Some broadly act as mutagens or carcinogens (causing DNA damage or mutations, which can lead to cancer), others can disrupt specific metabolic pathways, which can lead to dysfunction of particular biological systems such as the nervous system, liver, the kidneys or immune system.

Food intake is a major source of both toxin and toxicant exposure. Toxins can find their way into the diet by several routes, notably contamination by microorganisms, man-made toxicants (including pesticides, residues from food processing, prescription drugs and industrial wastes), or less frequently, contamination by toxins from other “non-food” plant sources. (1, 2) Some of the toxic heavy metals (lead, mercury, cadmium, chromium), while not “man-made,” have been released from the crust or via volcanoes (ie for mercury) and then redistributed into the environment at potentially dangerous levels. These chemicals can find their way into the diet as well. Microbial toxins, secreted by bacteria and fungi, can be ingested along with contaminated or improperly prepared food.

Even the method of food preparation via heat and otherwise has the potential for converting naturally-occurring food constituents into toxins. (3).  For instance, high temperatures can convert nitrogen-containing compounds in meats, coffee and cereal products into the potent mutagens benzopyrene and acrylamide, respectively. Smoked fish, including wild smoked salmon, and many cheeses, especially the processed cheese, can contain precursors to toxins called N-nitroso compounds (NOCs), which become mutagenic when metabolized by colonic bacteria.

Outside of the diet, respiratory exposure to volatile organic compounds (VOCs) is a common risk which has been associated with several adverse health effects, including but not limited to kidney damage, immunological problems, hormonal imbalances, blood disorders, and increased rates of asthma and bronchitis. (4)

One of the greatest sources of non-dietary toxicant exposure is the air in the home, that which can lead to wyat is called sick building syndrome. (5) Building materials (such as floor and wall coverings, particle board, adhesives, and paints) can “off-gas” releasing multiple toxicants that can be detected in humans. (6) For example, a toxic benzene derivative commonly used in disinfectants and deodorizers was detected in 98% of adults in the Environmental Protection Agency’s (EPA) “TEAM” study. (7)  In another EPA study, three additional toxic solvents were present in 100 percent of human tissue samples tested across the country. (8) And to make matters worse, I’ve heard recently over the radio that the CDC now recognizes that all American babies born in the USA have at least over 100 chemical toxicants. Other sources claim much more.

Futhermore, newly built or remodeled buildings can have substantial amounts of chemical “off-gassing” (9) Carpets can release several neurotoxins. In one published study, the testing of over 400 carpet samples showed neurotoxins to be present in more than 90 percent of the samples, quantitatively sufficient in some samples to cause death in mice. (10)  Even within the EPA headquarters where seventy-one ill employees evacuated the new EPA complex as a result of new carpet being installed. (11)

Carpets also trap toxicants like glyphosate that residents pick up on their feet and other environmental toxins from the air and ground. In this perspective, the “Non-Occupational Pesticide Exposure Study” (NOPES) found an average of 12 pesticide residues per carpet sampled, and determined that this route of exposure likely provides infants with nearly all of their non-dietary exposure to the notorious pesticides DDT, aldrin, atrazine, and carbaryl. (12). Bottom line, from the health viewpoint, it may be better to be poor and live in a mud house or cave and play in the dirt as our ancestors did for millions of years.

Section C

 Xenobiotic Metabolism in Evolutionary Perspective

The driving force in the evolution of sophisticated metabolic detoxification systems appears to be dependent on the ability of water to act as a solvent to dissolve toxic substances. Since cellular membranes are primarily lipid based and impermeable to most water soluble (scientifically: “polar”) substances, the transport of water-soluble compounds into a cell requires specialized transport proteins. By placing the appropriate transport proteins on the cell membrane, a cell will only allow desirable water-soluble molecules to enter, and will prevent entry of water-soluble toxins. This same mechanism also applies when the cell needs to excrete unwanted water soluble compounds (like cellular wastes); they exit the cell by a similar mechanism.

In contrast to water-soluble compounds, the lipid cell membrane presents little barrier to lipid-soluble compounds, which can freely pass through it. Potentially damaging lipid-soluble toxins can therefore gain free access to the cell’s inner home.  And these are much more difficult to remove.

Evolutionary biology fine-tuned the metabolic detoxification system by converting lipid-soluble toxins into inactive water-soluble metabolites. The “solubilization” of a toxin is accomplished by enzymes which attach (conjugate) additional water-soluble molecules to the lipid-soluble toxin at specific attachment points. If the toxin does not contain any of these attachment points, they are first added by a separate set of enzymes which chemically transform the toxin to include these molecular “handles”. Following the solubilization reactions, the chemically-modified toxin is transported out of the cell and excreted.

These three steps or phases of removing undesirable or harmful lipid-soluble compounds are performed by three sets of cellular proteins or enzymes, called the phase I (transformation) and phase II (conjugation) enzymes, and the phase III (transport) proteins.

Phase I, II, and III metabolisms have different biochemical requirements and respond to different metabolic signals, but must work in unison for proper removal of unwanted xenobiotics (such as toxins or drugs) or endobiotics (such as excess hormones). Enzymes of the phase I, II, and III pathways have several characteristics that make them well suited for their important roles. (13)  19

Unlike most other enzymes, detoxification enzymes; can react with many different compounds, thereby broadening the number of toxins a single enzyme can metabolize. They are also more concentrated in areas of the body that are most directly exposed to the environment (like the liver, intestines, or lungs). Accompanied with a feedback system, they are inducible, meaning that their synthesis can be increased in response to toxin exposure.

The liver is the primary detoxification organ; it filters blood coming directly from the intestines and prepares toxins for excretion from the body. Significant amounts of detoxification also occur in the intestine, kidney, lungs, and brain, with phase I, II, and III reactions occurring throughout the rest of the body to a lesser degree.

Section C

The Three Phases of Detoxification

Phase I Detoxification : Enzymatic Transformation

Under most circumstances, Phase I enzymes begin the detoxification process by chemically transforming lipid soluble compounds into water soluble compounds in preparation for phase II detoxification. The bulk of the phase I transformation reactions are performed by a family of enzymes called the cytochrome P450s (CYPs).

CYP enzymes are relatively non-specific and quite flexible, each has the potential to recognize and modify countless different toxins. A mere 57 human CYPs must be able to detoxify any potential toxin that enters the body. (14) With today’s 80,000 chemical toxicants released from today’s Industry, these 57 enzymes have to take time and energy off from their task of processing endotoxins, the body’s metabolic waste, to solubilize and excrete this onslaught of man-made toxicants.  

While the CYPs are able to mobilize en mass against the foreign “enemy”, the cost of this versatility is speed, as these CYPs metabolize toxins very slowly compared to other enzymes. For instance compare the predominant CYP3A4, which metabolizes 1-20 molecules per second, (15) to superoxide dismutase (SOD), which metabolizes over a million molecules per second. Major sites of detoxification overcome the slower speed by producing large amounts of CYPs – CYPs may represent up to 5% of total liver proteins, and similar large concentrations can be found in the intestines. CYPs are amongst the most well studied and best characterized detoxification proteins due to their role in the metabolism of prescription drugs, and to their role in metabolizing endogenous biochemicals (for example,the enzyme aromatase, which transforms testosterone to estradiol, is a CYP.) (16)”

Several other enzymes contribute to the phase I process as well, notably: the flavin monooxygenases (FMOs; responsible for the detoxification of nicotine from cigarette smoke); alcohol and aldehyde dehydrogenases (which metabolize drinking alcohol), and monoamine oxidases (MAO’s; which break down serotonin, dopamine, and epinephrine in neurons and are targets of several older antidepressant drugs) (17)

Phase II Detoxification – Enzymatic Conjugation

Following phase I transformation, the original lipid-soluble toxin has been converted into a more water-soluble form, however, this reactive intermediate is still unsuitable for immediate elimination from the cell for a couple of reasons: 1) phase I reactions are not sufficient to make the toxin water-soluble enough to complete the entire excretion pathway; and 2) in many cases, products from the phase I reactions have been rendered more reactive then the original toxins, which makes them potentially more destructive than they once were. Both of these shortcomings are addressed by the activities of the phase II enzymes, which modify phase I products to both increase their solubility and reduce their toxicity. For example,  the activation of the phase II enzymes is responsible for the anti-mutagenic and anti-carcinogenic properties of the metabolic detoxification systems. It is now widely accepted that phase II enzymes protect against chemical carcinogenesis, especially during the initiation phase of cancers. (18)

At the genetic level, the production of most phase II enzymes is controlled by a protein called nuclear factor erythroid-derived 2 (Nrf2), a master regulator of antioxidant response. (19) Under normal cellular conditions, Nrf2 resides in the cytoplasm (the liquid inside cells within which the cells components are contained) of the cell in an inactive state. (20) However, the presence of oxidative stress (triggered by metabolism of toxins by CYPs) activates Nrf2, allowing it to travel to the cell nucleus. (21)  In the cell nucleus, Nrf2 turns on the genes of many antioxidant proteins, including the phase II enzymes. (22) In this way, Nrf2 “senses” oxidative stress or the presence of toxins in the cell, and allows the cell to mount an appropriate response. Nrf2 regulates the activity of genes involved in the synthesis and activation of important detoxification molecules including glutathione and superoxide dismutase (SOD). It also plays an important role in initiating heavy metal detoxification, and the recycling of CoQ10, a potent antioxidant. (23, 24, 25)

Certain dietary constituents (including sulforaphane from broccoli and xanthohumol from hops) may also directly activate Nrf2 and stimulate antioxidant enzyme activity; this may partially explain their beneficial effects on detoxification.  (26)

There are several families of phase II enzymes that differ significantly in their activities and biochemistry. In several cases, phase II enzymes exhibit redundancy; a particular xenobiotic or endobiotic can be detoxified by more than one phase II enzyme.

UDP-glucuronlytransferases (UGTs) catalyze glucuronidation reactions, the attachment of glucuronic acid to toxins to render them less reactive and more water-soluble. There are several different UGTs that are distributed throughout the body, with the liver being the major location. In humans, many xenobiotics, environmental toxicants, and 40-70% of clinical drugs are metabolized by UGTs. (27)

In this perspective, the plasticizer bisphenol A (28)  and benzopyrene (from cooked meats) (29) are two notable examples of UGT substrates (a substrate is a molecule upon which an enzyme acts). Intestinal UGTs may affect oral bioavailability of several drugs and dietary supplements, and may be responsible for chemoprevention in  tissue. (30).

As for Glutathione S-transferases (GSTs), this enzyme catalyzes the transfer of glutathione (a significant cellular antioxidant) to phase I products. GSTs play a major role in the metabolism of several endobiotics, including steroids, thyroid hormone, fat-soluble vitamins, bile acids, bilirubin and prostaglandins. (31) GSTs can also function as antioxidant enzymes, detoxifying free radicals (32) and oxidized lipids or DNA. (33). GSTs are soluble enzymes that are ubiquitous in nature and in humans, forming about 4% of the soluble protein in the human liver and present in several other tissues (including brain, heart, lung, intestines, kidney, pancreas, lens, skeletal muscle, prostate, spleen and testes). (34, 35) Products of GST conjugation can be excreted via bile, or can travel to the kidneys where they are further processed and eliminated in urine.

Sulfotransferases (SULTs) attach sulfates from a sulfur donor to endo or xenobiotic acceptor molecules. This reaction is important both in detoxification reactions, as well as normal biosynthesis (the addition of sulfate to chondroitin and heparin, for example, is catalyzed by specific SULTs. (36) SULTs play a major role in drug and xenobiotic detoxification, and the metabolism of several endogenous molecules (including steroids, thyroid and adrenal hormones, serotonin, retinol, ascorbate and vitamin D). (37) SULTs in the placenta, uterus, and prostate are thought to play a role in the regulation of androgen levels. (38) In contrast to other phase II enzymes, SULTs can convert a number of procarcinogens (such as heterocyclic amines from cooked meats) into highly reactive intermediates which may act as chemical carcinogens and mutagens. (39)

While the UGTs, GSTs, and SULTs catalyze the bulk of human detoxification reactions, several other phase II enzymes contribute to the process to a lesser, but still important extent, including:

Methyltransferase enzymes catalyze methylation reactions using S-adenosyl-L-methionine (SAMe) as a substrate. COMT (catechol O-methyltransferase) is a major pathway for eliminating excess catecholamine neurotransmitters (such as adrenaline or dopamine). Methylation reactions are one of the few phase II reactions that decrease water solubility (40)

Arylamine N-acetyltransferases (NATs): NATs detoxify carcinogenic aromatic amines and heterocyclic amines (41)

Amino acid conjugating enzymes: Acyl-CoA synthetase and acyl-CoA amino acid N-acyltransferases attach amino acids (most commonly glycine or glutamine) to xenobiotics. The food preservative benzoic acid is one example of a toxin metabolized by amino acid conjugation. (42)

Phase III Detoxification – Transport

Phase III transporters are present in many tissues, including the liver, intestines, kidneys, and brain, where they can provide a barrier against xenobiotic entry and a pump system to pump out endobiotics. (43) Since water-soluble compounds require specific transporters to move in and out of cells, phase III transporters are necessary to excrete the newly formed phase II products out of the cell. Phase III transporters belong to a family of proteins called the ABC transporters (for ATP-Binding Cassette (44)), because they require chemical energy, in the form of ATP, to actively pump toxins through the cell membrane and out of the cell. (45) They are sometimes called the Multidrug Resistance Proteins (MRPs), because drug-resistant cancer cells use them as protection against chemotherapy drugs. (46)

In the liver, phase III transporters move glutathione, sulfate, and glucuronide conjugates out of cells into the bile for elimination. In the kidney and intestine, phase III transporters can remove xenobiotics from the blood for excretion from the body. (47)

Balance of Phase I and Phase II Reactions

The products of phase I metabolism are potentially more toxic than the original molecules, which does not present a problem if the phase II enzymes are functioning at a rate to rapidly neutralize the phase I products as they are formed. This, however, is not always the case. Factors which increase the ratio of phase I to phase II activity can upset this delicate balance, producing harmful metabolites faster than they can be detoxified, and increasing the risk of cellular damage.

Some of the factors include: diet (some foods and supplements increase phase I enzyme activity), smoking and alcohol consumption (both induce phase I, so wine in moderation can be good), age (which can decrease phase II UGT, GST, and SULT activity), sex (premenopausal women show 30-40% more phase I CYP3A4 activity than men or postmenopausal women), disease, and genetics.

An illustrative example of the consequences of phase I/phase II imbalance is toxicity caused by overdose of the analgesic acetaminophen (paracetamol) – the active ingredient in Tylenol®. Acetaminophen toxicity is the most common cause of liver failure in the US. (48) With a normal therapeutic dose of acetaminophen, the drug is predominantly detoxified by the phase II UGT and SULT enzymes. A small amount of the drug is detoxified by a third mechanism: it is first transformed into the toxic metabolite NAPQI (N-acetyl-p-benzoquinoneimine) by phase I CYP enzymes; and this intermediate is detoxified by conjugation with glutathione using the phase II enzyme GST.

During acetaminophen overdose, the UGT and SULT enzymes become quickly overwhelmed. Proportionally more of the drug undergoes the third detoxification mechanism (transformation to NAPQI and conjugation by GST). Eventually, activity of the phase II GST enzyme slows as glutathione stores become depleted (49), and NAPQI is produced faster than it can be detoxified. Rising levels of NAPQI in the liver cause widespread damage, including lipid peroxidation, inactivation of cellular proteins, and disruption of DNA metabolism. (50) Treatment for acetaminophen overdose involves the timely replenishment of glutathione stores through administration of the precursor amino acids for glutathione synthesis (most commonly N-acetyl cysteine (51)

Complementary Mechanisms of the Detoxification Process

Following are several other mechanisms work in concert with the phase I, II, and III enzyme systems to improve their efficiency as well as to extend their functionality. While not officially characterized as part of xenobiotic metabolism, they are nonetheless important for reducing or mitigating toxin exposure.

Bile secretion is a critical digestive process for the absorption of dietary fats and fat-soluble nutrients. Bile also functions as the major mechanism for moving conjugated toxins out of the liver and into the intestines, where they can be eliminated.

Antioxidation is a necessary protective measure against the harsh phase I oxidation reactions, which frequently produce free-radical byproducts. The production of antioxidant enzymes, many of which are under the same genetic regulation (by Nrf2) as the phase II enzymes, is important for minimizing this free-radical damage.

Heavy metal toxicity can lead to oxidative damage by direct generation of free radical species and depletion of antioxidant reserves. (52) Mercury, arsenic, and lead, for example, effectively inactivate the glutathione molecule so it is unavailable as an antioxidant or as a substrate for xenobiotic detoxification (53). This can also reduce the activity of the enzymes that recycle glutathione (54) One method for heavy metal removal is their chelation by the cellular proteins metallothioneins (MTs), which have a high capacity to bind various reactive metal ions, such as zinc, cadmium, mercury, copper, lead, nickel, cobalt, iron, gold, and silver. (55) One molecule of MT can bind 7–9 zinc or cadmium ions (or any combination of these two), up to 12 copper ions, and up to 18 mercury ions. (56) Cellular stress (particularly oxidative stress), turns up MT production, which, like the phase II enzymes, is stimulated by the activity of Nrf2. (57)

Prevention of absorption through trapping of potential toxins (such as surface adhesion to another molecule in the gut, like activated charcoal or kaolin clay (58)) is an effective means of mitigating exposure; this mechanism has the requirement of some dietary adsorbent to be taken while the toxin is in transit in the GI tract. Uptake of potential toxins and their detoxification by beneficial colonic microflora could have a similar effect.

Conclusion

To summarize the key points, metabolic detoxification is centered on the biochemical process of removing unwanted lipid-soluble compounds from the body. These “unwanted” compounds can be foreign (such as an environmental toxicants) or endogenous (toxins; such as excess hormone) in nature. Detoxification reactions occur throughout the body, with the liver being the predominant detoxifying organ. Detoxification reactions follow three steps or “phases” that have the ultimate goal of converting the toxin into an inert, water-soluble form for excretion: Phase I reactions transform the toxin into a chemical form that can be metabolized by the phase II enzymes. Phase I reactions are performed primarily by the cytochrome P450 enzymes. Phase II reactions conjugate (attach) the toxin to other water-soluble substances to increase its solubility. Each of the different types of phase II enzymes catalyzes a different type of conjugation reaction. UDP-glucuronlytransferases (UGTs) catalyze the glucuronidation of most clinical drugs, and several environmental toxins. Glutathione-S-transferases (GSTs) conjugate toxins with the antioxidant glutathione; they can also directly detoxify free radicals. Sulfotransferases (SULTs) catalyze sulfonation reactions; they may also be important for controlling sex hormone levels. Other types of phase II reactions that are used less frequently include methylation and amino acid conjugation reactions. Phase III detoxification involves the transport of the transformed, conjugated toxin into or out of cells. Different phase III transport proteins work in concert to shuttle toxins from different parts of the body into bile or urine for excretion.

Following detoxification reactions, the toxins are removed from the body by excretion: First off, products of liver detoxification often leave the body by being secreted into the intestines in bile, but can sometimes be transported into the bloodstream for processing by the kidneys. Thereafter, the cells that line the intestines can detoxify toxins as they are absorbed, and release them back into the intestinal lumen. Lastly,  the kidneys can filter and further process toxins from circulation, excreting them from the body as urine.

Metabolic detoxification is one of the most important restorative and longevity optimization functions that all sentient beings can modulate favorably. As Jean Bernard stated often, it’s all a question of the milieu’s back and forth struggle, the body’s anabolic and catabolic ups and downs, to compensate and restore homeostasis, the dynamic equilibrium of Life, at least for a few more milllions of years until Humans will be able to shift into the unified twilight zone.

Ch. Joubert (Director of H.M. Institute)

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Disclaimer: Nothing in this educational blog should be construed as medical advise. Only the State controlled certified synthetic drug and surgery pushing conventional doctors have the monopoly of “real” medicine, the result of which is to have become one of the first causes of collective suffering and premature death ever.
2018 (c). Happiness Medicine Institute et al.

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