The Detoxification and Biotransformation System in the Human Body

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Detoxification Pathways

There are 6 main detoxification organs or systems in the human body:

  • Liver (processes and packages toxins) (70% of detoxification)
  • Lungs (gas exchange of oxygen and carbon dioxide)
  • Gastrointestinal Tract (excretes waste)
  • Skin (sweat)
  • Kidneys (urination)
  • Endothelial cells of the blood brain barrier

The intestines, liver and kidneys are the primary organs of detoxification.

Biotransformation enzymes exist in the smooth endoplasmic reticulum, cystosol (intracellular fluid) and to a lesser degree in the membranes of the mitochondria, nuclei and lysosomes (small spherical organelles) of the liver’s hepatocytes. The kidneys and lungs are the next major biotransformation sites, but only at 10 – 30% of the livers capacity. The skin, nasal mucosa and intestinal mucosa also have some biotransformation capacity.

Other sites of detoxification metabolism include epithelial cells of the gastrointestinal tract, lungs, kidneys, and the skin. These sites are usually responsible for localized toxicity reactions.

Once an unwanted compound has been completely bio transformed and removed from the cell, it will then be eliminated from the body via – kidneys, bowels, breath, sweat, saliva or hair – completing the detoxification process.

Toxins that the body is unable to eliminate build up in the tissues and typically stored in the adipose (fat) tissue.

Liver Detoxification

Almost 2 quarts of blood pass through the liver every minute for detoxification. Filtration of toxins is absolutely critical for the blood from the intestines because it is loaded with bacteria, endotoxins, antigens – and tight body complexes, and various other toxic substances.

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Figure 1:  Detoxification pathways

Intermediary Metabolites  and Pathological Detoxifiers

The transformation of xenobiotics into more chemically active toxins can cause several problems. A significant side effect of all this metabolic activity is the production of free radicals as xenobiotics are transformed by phase 1. Without adequate free radical defenses, every time the liver neutralizing toxins, it is damaged by the free radicals that are produced.

The most important antioxidant for neutralizing free radicals produced by phase 1 byproducts is glutathione. In the process of neutralizing free radicals glutathione is oxidized to glutathione disulfide. Glutathione is required for one of the phase 2 detoxification processes namely glutathione conjugation. When high levels of toxic exposure produces so many free radicals from phase 1, all of glutathione is used up, and glutathione conjugation stops working.

Another potential problem occurs because the toxins transformed into intermediary metabolites by phase 1 can be more toxic than the original toxin. Unless these intermediary metabolites are quickly removed from the body by phase 2 detoxification pathways, they can cause widespread problems. Therefore, the rate at which phase 1 produces intermediary metabolites must be balanced by the rate at which phase 2 finishes the process. Unfortunately, some people have a very active phase 1 detoxification system but very slow phase 2 enzymes. These people are described as “pathological detoxifiers” because they’re over active phase 1 results in a buildup of more harmful intermediate products, which phase 2 cannot detoxify quickly enough. The end result is that these people suffer severe toxic reaction to environmental poisons.

Gastrointestinal Tract Detoxification

About 25% of detoxification occurs within the cells lining the intestines, the remainder occurs in the liver.

Most literature on detoxification refers to liver enzymes, as the liver is the site of the majority of detoxification activity for both endogenous and exogenous compounds. However, the first contact the body makes with the majority of xenobiotics is the gastrointestinal tract. the gastrointestinal tract is the second major site in the body for detoxification. Detoxification enzymes such as Cyp3A4 and the antiporter  activities have been found in high concentrations at the tip of villi in the intestine.

Adequate first pass metabolism of xenobiotics by the gastrointestinal tract requires integrity of the gut mucosa. Compromised barrier function of the mucosa will easily allow xenobiotics to transit into the circulation without opportunity for detoxification. Therefore, support for healthy gut mucosa is instrumental in decreasing toxic load.

The gastrointestinal tract influences detoxification in several other ways. Gut microflora can produce compounds that either induce or inhibit detoxification activities.

Pathogenic bacteria can produce toxins that can enter circulation and increase toxic load.

Detoxification through the intestinal tract is enhanced by fasting, mono, high fiber and mucus-less diets, ingestion of substances such as charcoal, mud and grasses, and in some cases by the use of cathartics that either lubricate, increase fluidity, add bulk or stimulate peristaltic motion.

Gastrointestinal health and gut permeability also play a role in detoxification. Increased gut permeability allows for increased absorption of xenobiotics and toxins, which are processed and removed by the liver, thus increasing the demands on the liver detoxification system. Impaired gastrointestinal integrity can be improved via dietary support as well as prebiotics and probiotics.

Fiber is particularly important for supporting detoxification. Dietary fibers bind not only carcinogens, bile acids, and other potentially toxic agents, it also promotes a faster transit time and therefore less opportunity for toxin interaction with the intestinal lining and reabsorption. In addition, increased fiber intake helps positively balance the intestinal microflora, which minimizes endotoxin production from pathogenic bacteria.

Brain Detoxification: The Glymphatic System

The cytochrome P450 enzyme system is found in other parts of the body, especially the brain cells.

The glymphatic system (or glymphatic clearance pathway) is a functional waste clearance pathway for the mammalian central nervous system (CNS). The brain is not part of the body’s lymphatic system which is responsible for removing extracellular proteins, excess fluid, and metabolic waste products from peripheral tissues.

Glymphatic flow answers the long standing question of how the sensitive neural tissue of the CNS functions in the absence of a conventional lymphatic circulation. The pathway consists of a para-arterial influx route for cerebrospinal fluid (CSF) to enter the brain parenchyma, coupled to a clearance mechanism for the removal of interstitial fluid (ISF) and extracellular solutes from the interstitial compartments of the brain and spinal cord. Exchange of solutes between the CSF and the ISF is driven by arterial pulsation and regulated during sleep by the expansion and contraction of brain extracellular space.

Clearance of soluble proteins, waste products, and excess extracellular fluid is accomplished through convective bulk flow of the ISF, facilitated by astrocytic aquaporin 4 (AQP4) water channels.

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Figure 2:  Mammalian Gymphatic System

A publication by L. Xie and colleagues in 2013 explored the efficiency of the glymphatic system during slow wave sleep and provided the first direct evidence that the clearance of interstitial waste products increases during the resting state. Xia and Nedergaard demonstrated that the changes in efficiency of CSF–ISF exchange between the awake and sleeping brain were caused by expansion and contraction of the extracellular space, which increased by ~60% in the sleeping brain to promote clearance of interstitial wastes such as amyloid beta.

During the night, we experience sleep cycles that average about 90 minutes. In the first half of the night we cycle through all of the stages, N1, N2, N3, and REM sleep. Slow wave sleep or delta sleep is N3. We start at N1 and go deeper into N2, then deeper into N3, the stage where brain cleansing occurs. In the second half of the night, REM sleep increases and alternates with N1 and N2 sleep, so it appears most of the cleanup is done in the first half of the night.

The interstitial space makes up about 20% of the brain volume but that fraction varies over the course of the day and night. During sleep this space increases by up to 60% in volume. This flushing of the glymphatic system removed waste metabolic products that are potentially neurotoxins. These products include β-amyloid proteins which are strongly suspected to play a part in Alzheimer’s Disease.

This is a two part process:

  • 1. After the brain cells shrink 60 %  cerebral spinal fluid is pumped through the brain’s tissue, then 
  • 2. The waste is flushed back into the circulatory system where it enters the blood circulation system and goes to the liver

Cerebral spinal fluid quickly flows into the space, aided by the pulse of the arteries. It mixes with the interstitial fluid and washes the waste toward the veins and carries it to the liver. This process occurs during slow wave sleep, the deepest sleep.

Another startling finding was that the cells in the brain “shrink” by 60 percent during sleep. This contraction creates more space between the cells and allows CSF to wash more freely through the brain tissue. In contrast, when awake the brain’s cells are closer together, restricting the flow of CSF. 

The researchers observed that a hormone called noradrenaline is less active in sleep. This neurotransmitter is known to be released in bursts when brain needs to become alert, typically in response to fear or other external stimulus. The researchers speculate that noradrenaline may serve as a “master regulator” controlling the contraction and expansion of the brain’s cells during sleep-wake cycles.

Using these techniques, researchers were able to observe in mice – whose brains are remarkably similar to humans – what amounts to a plumbing system that piggybacks on the brain’s blood vessels and pumps cerebral spinal fluid (CSF) through the brain’s tissue, flushing waste back into the circulatory system where it eventually makes its way to the general blood circulation system and, ultimately, the liver.

Skin Detoxification

Detoxification through the skin is facilitated by the promotion of sweating. This can be accomplished by ingesting sudorific (diaphoretic) herbs like ginger, mustard and cayenne, either by themselves or in conjunction with fasting, saunas, baths and sweats.

Packs of clay, mud, salt, charcoal, seaweed, volcanic ash and castor oil have also proven useful in increasing the elimination of toxins through the skin.

Physiological Factors that Affect Detoxification

There are various physiological and pathological factors that affect the detoxification process. Physiological factors that can influence detoxification include:

  • Age
  • Genetic Factors
    • Polymorphisms (SNPs)  

Aging

The activity of phase I detoxification enzymes decreases in old age. Aging also decreases blood flow through the liver, further aggravating the problem. Lack of the physical activity necessary for good circulation, combined with the poor nutrition commonly seen in the elderly; add up to a significant impairment of detoxification capacity, which is typically found in aging individuals.

Genetic Factors

Biochemical individuality is a simple concept that states all humans differ biochemically from others. And that biochemical individuality directly affects the degree to which a chemical compound is bio-transformed from person to person. Some of the factors that determine a person’s level of biochemical individuality and therefore biotransformation capacity are:

The structure, amount of or complete lack of a specific biotransformation enzyme may differ among individuals and this can give rise to differences in rates of biotransformation.  Genetic differences in the ability of an individual to metabolize xenobiotics are related to the presence of different versions of the gene encoding that activity, or genetic polymorphism.

A Single Nucleotide Polymorphism, also known as Simple Nucleotide Polymorphism, is a DNA sequence variation occurring commonly within a population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes.

Polymorphisms (SNPs) in the genes coding for a particular enzyme can increase or, more commonly, decrease the activity of that enzyme. Both increased and decreased activity may be harmful. As mentioned above, increased Phase I clearance without increased clearance in Phase II can lead to the formation of toxic intermediates that may be more toxic than the original toxin. Decreased Phase I clearance will cause toxic accumulation in the body.

Genova Diagnostics offers a comprehensive test of the Polymorphism (SNPs) in its DetoxiGenomic(TM) Profile. 

Click the link to view a Sample Report