Detoxification and Drainage

A Theoretical and Practical Approach

The Physiology of Detoxification

       In the previous chapter we saw that the body is esposed to a wide variety toxins present in the air, water, soil and food. The body has several inherent defense mechanisms and membrane barriers to prevent the absorption and distribution of the toxin when the intoxication has occurred. Once inside the body, the internal defense system, or Basic Bioregulatory System will be mobilized in order to eliminate the toxin or at least try to compensate for it.

       In this chapter, We will look at the way the body deals with these toxins. Before a toxin can have a detrimental effect on the body, it needs to reach the target organ or cell. In principle four steps are necessary for this:

- Absorption

- Transport

- Metabolism

- Distribution and storage

- Elimination

       Toxicokinetics studies the absorption, distribution, elimination, metabolism and/or clearance that take place in the body after exposure to the toxin. Toxicodynamics on the other hand studies the biochemical and physiological effects of drugs and toxicants and determines their mechanism of action. Toxicokinetics can also be seen in the diagram below.

       1 Absorption

       Toxins can enter the body through all the surfaces which are in contact with the outside world. These comprise the skin, the mucous membranes and also the gastrointestinal tract. In general, the absorption over the respiratory mucosa is the quickest, whereas it is the slowest over the dermal route. The overall entry depends on the amount of toxins present, but also on the saturability of the transport process.

       The mucosal surfaces have several barriers which will prevent toxins from entering the body, such as a mucosal barrier, the physical presence of symbiotic bacteria as well as the so-called tight junction. The skin also has barriers in the form of a certain level of pH, etc.

       2 Transport

       Once the toxicant is absorbed into the body it moves around in two ways, either by bulk transfer via the blood or lymph, but also locally through diffusional transfer over short distances. The path which a toxin takes after absorption is illustrated in Fig.II,2.

       During absorption, distribution and elimination, a toxin will encounter various cell membranes before interacting with the target tissue. These membrane barriers will differ from relatively thick areas of the skin to relatively thin lung membranes, in all cases though the composition is relatively similar.

       The cell membrane can be seen as a lipid matrix. If contains both phospholipids (hydrophobic) portions as well as hydrophilic heads. Intra- and extracellular proteins transverse the membrane.

       This will differ from organ to organ. The myelin in the brain consists of 100% lipid bilayer whereas mitochondria have only a 40% lipid bilayer. This, of course has implication for the distribution of fat soluble toxins. Depending on the fat solubility of the toxin, it will thus transverse the cell membrane. Many of the proteins which tranverse the membrane are active in transport of toxins over the cell membranes.

       The distribution of the absorbed toxin will depend on various factors, such as physiological factors, but also the phyusiochemincal properties of the drug. This process is thus a REVERSIBLE movement of the toxicant between the blood and tissues and between the extracellular and intracellular compartment. The velocity at which this movement is reversible becomes important when we address the mobilization and drainage of toxins later on.

       Factors which can complicate the distribution of a toxin can be the following:

- Perfusion of the organ

          The well perfused tissues include the liver, kidneys and brain; whereas the low perfused tissues include the bone and fat tissue where there is slow elimination from these tissues.

- Protein Binding

          There also may be significant protein binding which could affect the delivery of the drug to the tissues and vice versa. Especially binding of toxins to the matrix structures may trap these toxins there for years and prevent elimination.

       Protein binding also plays a very important role in the transport of toxins. There are many plasma proteins involved in such a transport, but mostly involved are albumin, alpha-acid-glycoprotein, the lipoproteins, and globulins.

       The lipoproteins, such as HDL,LDL and VLDL are very important here, as so many toxins are lipophilic, and therefore they will carry a number of toxins. Iron and copper will again be carried by the metal binding globulins, transferring and cereluplasmin.

       3 Distribution and Storage

       Plasma protein binding is not selective and toxints can thus compete with each other and even with endogenous substances for binding. Covalent binding to the protein forms a minor part, but the dissociation I extremely difficult and the carrier molecule is changed, and may eventually play a role in carcinogenesis.

       Noncovalent binding is more common. The toxin can dissociate easier from this bond. However, in some cases the bond may be so strong that the toxin remains bound for weeks, months or years. Certain metals have high association constants and their dissociation is extremely slow.

       If the affinity for an organ is large, the toxin will accumulate or form a depot for years. In general, lipid insoluble toxicants stay in the plasma and interstitial fluids, while lipid soluble contaminants reach all compartments, and may accumulate in fat.

       Some toxins have specific affinity for certain tissues. Tetracyclines have a high affinity for the calcium containing tissues, which is seen in the discoloration of teeth if it is given under the age of 14 years. Similarly, the anti-malarial, chloroquine has an affinity for the melanin, and can be taken up by tissues like the retina, causin a retinitis. This drug is often used in lupus and other connective tissue diseases, which makes an ophthalmic check up every six months mandatory.

       Bone will also concentrate certain toxicants such as lead where a sudden loss of bone can lead to acute release of the toxin and have dire consequences, especially after menopause when there may be a sudden bone loss.

       This will be discussed later when we look at the indeal rates of detoxification.

       Lipophilic pesticides, such as the organochlorines and PCB’s can be expected to accumulate in fat tissues.

       The affinity of metals to SH groups have also been addressed in the previous chapters.

       The binding of these metals to the numerous thiol groups in the extracellular matrix is of special concern.

       Certain areas will be naturally less penetrable to toxins. The brain, which is protected by the blood brain barrier, is such an example. Disease processes such as meningitis and other inflammatory or infective processes can disrupt this barrier and thus cause toxins to enter the brain tissue.

       Other tissue blood barriers include the prostate/blood barrier and the testis/blood barrier.

       Unfortunately, other than what is generally believed, the placenta is a poor barrier and the fetus is thus exposed to all the toxins to which the mother is exposed. This has been seen in fat tissue biopsies which were performed on newborns and found numerous toxins such as PCB’s, dioxin and others in the tissues. We need thus to assume in today’s environmental pollution, that our newborns are already contaminated with toxins.

       4 Metabolism of Toxins

       One of the most important determinants of the persistence of toxins in the body is the extent to which they can be metabolized and excreted.

       Several families of metabolic enzymes are active in metabolism of endogenous and exogenous toxins.

       These include one of the most important, the P450 system, but also the flavin containing monooxidases(FMO’s), the alcohol and aldehyde dehydrogenases, amine oxidases cyclooxygenases, reductases, hydrolases and the conjugating enzymes such as the methyltransferases as well as the glutathione transferases to name a few.

       Most of the metabolism takes place in the liver, and as most of the toxins entering the body are lipophilic, they need to become water soluble for excretion. After entrance to the liver and other organs, xenobiotics may undergo two phases of metabolism.

       4.1 Phase I Reactions

       Phase I metabolism involves mainly the CYP(P450) system, the FMO’s and the hydrolases. Following the addition of a polar group, conjugating enzymes typically add more constituents, such as sugars, sulfatesor amino acids which make the compound more water soluble.

       In this process, however sometimes more toxic intermediate metabolites are formed, these then will have to be detoxified again. These intermediate metabolites are likely to react with nudear parts of macromolecules unless they are further detoxified. An example is the breakdown of alcohol to acetaldehyde, which is much more toxic that the alcohol.

       The CYP system or P450 plays a very important role in the phase I reactions. The CYP’s which constitutes the carbon monoxide-binding pigment of the liver microsomes are heme proteins. A nomenclature has been developed for the different types and isoforms.

       Although mammals are known to have 18 CYP families, only three are responsible for xenobiotic metabolism. The remaining are involved in steroid hormone production. They are classified according to the gene, subfamily and lastly the isoform (Arabic numeral, letter, Arabic numeral).

       Thus CYP 3 A 4 is responsible for the metabolism of many drugs as well as endogenous toxins and exogenous toxins.

       Its activity can also be influenced by a host of drugs and chemicals, and it can either be induced, which will have the result that certain drugs are broken down too quickly, e.g., warfarin, whereas grapefruit juice in large quantities is known in fact to damage this system irrevocably and thus may lead to an accumulation of drugs.

       The Phase I detoxifying pathway takes care of environmental toxins such as pesticides, pollutants and food additives as well as drugs and alcohol. The end products of uur own metabolism are also processed here for excretion. Fat soluble toxins are changed by way of oxidation, reduction and hydrolysis to make them more water soluble for excretion via the bile and the kidney.

       It is important to note that these enzymes need certain co-factors to fulfill their action. These are trace elements, vitamins, amino acids and substances like NADH.

       Phase I produces significant amounts of free radicals during this detoxification processs, and if the antioxidant status of the patient is not adequate tissues damage may occur if the P450 is overloaded, or induced. Some substances, such as caffeine, alcohol, certain drugs, dioxin and organophosphates (used as pesticides), and paint fumes can induce this pathway. Sometimes intermediate substances like the acetaldehyde formed during the metabolism of certain toxins, like alcohol, can be more toxic to the body than the original substance. Certain people, called fast acetylators, will then be more prone to damage of the liver, as the toxin is fast metabolized to this dangerous intermediate, and then the process is slow again. These individuals are at higher risk for liver damage during ingestion of toxins which will use the alcohol dehydrogenase pathway to be detoxified, for example when paracetamol overdose occurs.

       4.2 Phase II Reactions

       The Phase II pathway or conjugation pathway uses substances rich in sulfhydryl groups to metabolize toxins. A number of these substances, like cysteine and taurine as well as glutathione which are formed from glycine, glutamine and cysteine under influence of a selenium dependent enzyme, also act as free radical scavengers and heavy metal chelators. During conjugation of toxins they are lost to the body forever, as they are excreted with the toxin, whereas as free radicals they can be regenerated. Some substances will only use phase I or phase II to be detoxified, others will use both. It is thus clear, that if the phase II pathway is overloaded, the free radical scavenging ability will be given up in favor of the conjugation function and further damage to the liver parenchyma may occur. Also if the patient is deficient in selenium for instance, glutathione production will be impaired, with the resultant of toxicity and free radical damage.

       5 Elimination

       After the toxins have gone through these two phases, they are ready to be eliminated. However, if the intermediary toxin is not broken down, or the toxin load is too high there will be bioaccumulation of the toxin.

       The ability to detoxify and eliminate toxins is paramount to the maintenance of health in an organism.

       For unicellular organisms a simple process of diffusion is enough to eliminate toxins, however, multicellular organisms, especially if there has been an increase in complexity, needs to find other ways to eliminate toxins.

       With an increase in complexity, organisms have developed an increase in size, a decrease in surface area to body mass ratio, compartmentalization of cells and organs, as well as an increase in lipid content. Together with the fact that organisms neeed to protect themselves from the environment with barriers such as scales and skin, means that there is less possibility for toxins to diffuse out of the body. This was solved, by developing specialized methods of metabolism for toxins and specialized routes of elimination. We have thus major and minor elimination routes.

       The major routes involve the liver, the kidneys, the mucous membranes and the lungs as well as the skin, whilst the minor routes involve the saliva, sweat, milk, hair, and secretion from reproductive organs.

       To eliminate the toxin, it must go through the reverse route as was described in section II from the place of storage back to the external environment.

       Chemicals ard transported from the place of storage mainly via the blood stream. As the circulatory system leans itself toward the transport of water soluble substances, the more lipophilic substances ard, the less likely they are to freely diffuse into the blood and thus the mobilization of these toxins from their place of storage is more difficult. The same process as was discussed in section II, where binding of toxins to carrier proteins and lipoproteins is the way these toxins will enter the blood steam.

       The toxins are thus transported back to the organs of elimination, but if these organs are dysfunctional, overloaded or damaged, the toxins cannot be excreted. This means that such toxins will circulate further in the blood stream and through diffusion enter some compartments again, e.g. a fat soluble toxin may now be stored in the brain, with dire consequences. The stimulation of toxins out of their compartments should thus be a slow and careful process.

       Here we distinguish two groups of compartments:

       1 The rapid-exchange system

       In these compartment, tissue concentration of toxicant is similar to that of the blood

       2 The slow-exchange system

       In these compartments, tissue concentration of toxicant is higher than in blood due to binding and accumulation-adipose tissue, skeleton and kidneys can temporarily retain some toxins, e.g. arsenic and zinc.

       The important fact is that Detoxification and Drainage should carry on so long till the slow exchange system is given a chance to give up all the toxins. The organs involved in the Detoxification and Drainage of the toxins will be discussed in the next section.

       Conclusion

- Toxins have to cross several membranes in the body to be absorbed,      and to    eventually be stored, or eliminated via the organs of elimination.

- Toxins follow simple kinetics, and observe the diffusion over semi-permeable membranes till a steady state is achieved on both side of the membrane.

- These basic kinetics are different for toxins who has a high association co-efficient with proteins and cellular structures, be it in the blood or in the organ of storage.

- These kinetics affect both the storage and the mobilization of toxins in and out of these compartments and needs to form the basis on which the practical Detoxification and Dralinage is executed.

- Two groups of compartments can be distinguished, depending on the perfusion of the organ and the amount of toxin bound to protein.

                     - The rapid-exchange system.

                        In these compartments, tissue concentration of toxin is similar

   to that of the blood.

- The slow-exchange system

In these compartments tissue concentration of toxin is higher than in blood due to binding and accumulation.

- Many toxins are metabolized before they can get excreted.

   One of the main purposes of this is to render fat soluble

   toxins water soluble for excretion in the bile and kidneys.

- The P450 system of enzymes plays a major role here,

   especially in the liver, where it comprises the phase I

   reactions. This is augmented by the phase II reactions.

- Organs are at danger during the act of Detoxification and

   Drainage, due to the high concentration of toxins moving

   through the organ at the time, and through the generation of

   free radicals during the detoxification process.

- Support of theses organs is thus of utmost importance during

   detoxification and the elimination of the toxin.