Phases Of Detoxification
There are two fundamental stages of the detoxification process that cleanses our entire system - Phase I plus Phase II. These phases are basically two dissimilar biochemical processes that facilitate the body to get rid of all xenobiotics (foreign chemical substances in the body) as well as other harmful chemicals.
Phase I detoxification
During the first stage of detoxification, chemicals that are non-polar and not soluble in water are transformed into comparatively electrically charged or polar amalgams with assistance from enzymes that append a reactive or polar group. In this phase, molecules are prepared in such a manner that relatively smaller molecules may be appended or changed during the second phase of detoxification when the chemicals become water-soluble, making it possible for the body to excrete them naturally. The modifications that occur during the Phase I comprise a form of chemical reaction called biotransformation. The characteristic changes that most of the chemicals undergo during Phase I comprise oxidation reactions (wherein the chemicals lose electrons) and reduction reactions (during which chemicals gain electrons).
Oxidation reactions include a number of processes, such as dehalogenation, desulfuration, deamination, hydroxylation, and sulfoxidation. Dehalogenation does away with a halogen group, which comprises chlorine, fluorine, iodine or bromine, while appending an oxygen group. Desulfuration, as the name suggests, only gets rid of a sulfur group, while hydroxylation appends a hydroxyl group comprising oxygen and hydrogen. An amino group, comprising a combination of nitrogen and hydrogen in the form of NH3, is removed during deamination, while sulfoxidation appends an oxygen molecule to a sulfur group.
Reduction reactions involve azo reduction, aromatic nitro reduction, reductive halogenations as well as aldehyde and ketone reduction. During the azo reduction, a N2 (nitrogen-to-nitrogen) bond is split up, while aromatic nitro reduction transforms NO2 (nitrogen dioxide) into an amide (NH2). During the reductive halogenations, a halogen group is replaced with a hydrogen molecule. The aldehyde and ketone (an organic chemical amalgam) reduction involves converting aldehydes and ketones into an alcohol.
Phase I detoxification is made possible by no less than 50 enzymes belonging to 10 families and controlled by 35 dissimilar genes. The most important enzymes that are needed for Phase I detoxification to take place include the cytochrome P-450 monooxygenase system as well as the mixed-function amine oxidase system. The cytochrome P-450 enzyme comprises the basic system and it initiates and catalyzes the Phase I detoxification process. On the other hand, the enzyme called mixed-function amine oxidase system decontaminates the chemical groups known as amines, which comprise hydrogen and nitrogen.
Cytochrome P-450 enzymes exist in several different forms and many of these take part in the Phase I detoxification processes. This enzyme is present in highest concentration in our liver - the most dynamic metabolism site in our body. Our lungs and kidneys, which possess a third of the detoxification capacity of the liver, form the secondary organs that are involved in biotransformation. Some amounts of cytochrome P-450 are also present in the brain, muscles, skin, intestines, spleen, heart, adrenal cortex as well as the testes.
Availability of a variety of minerals has a direct effect on the activities of the detoxification enzymes. For instance, the enzyme called alcohol dehydrogenase, which transforms alcohols like ethanol into aldehydes by means of an oxidation reaction, functions properly only when sufficient supplies of zinc are available. In the subsequent metabolic phase, the enzyme called aldehyde oxidase transforms aldehyde into an acidic substance, which can be eliminated from the body along with urine. The actions of the enzyme aldehyde oxidase are subject to ample supplies of iron and molybdenum. Detoxification enzymes also require several other minerals, including copper, magnesium, manganese, selenium and sulfur, for their proper functioning.
Generally, the actions of the enzymes during the Phase I detoxification reduce the chemical toxicity. Nevertheless, the possibility of formation reactive or toxic chemicals cannot be ruled out during the Phase I and compared to the original chemicals these compounds can be more toxic. This phenomenon is called bioactivation. Usually when the Phase II detoxification process is in progress, such chemicals are turned into harmless compounds and eliminated from the body. Nevertheless, in case of any discrepancy in the Phase I and Phase II detoxification active levels, such toxins will linger in the body. It may be noted that any imbalance between detoxification during Phase I and Phase II is related to augmented symptoms of endocrine, immune, and nervous system toxicity.
Several toxic chemicals are formed during the Phase I detoxification and some of them include mutagens (leading to cell mutation), teratogens (leading to malformation of the fetus) and carcinogens (responsible for cancer). For instance, a chemical present in second hand cigarette smoke as well as coal tar and called benzo[a]pyrene remains inert biologically till it is transformed into a metabolite, which has the aptitude to initiate activities that cause cancer, by the mixed-function amine oxidase system. Several other chemical compounds also result in the formation of harmful and reactive free radicals during the course of the Phase I detoxification. When there is an accumulation of free radicals in our body it enhances the chances of developing cancer.
It is possible to calculate the functioning level of Phase I detoxification by undertaking an easy caffeine metabolism examination. This test involves ingesting a known amount of caffeine and taking samples of saliva twice at particular intervals. There is a direct relation between the effectiveness of caffeine clearance and Phase I detoxification competence. Rapid clean up of caffeine demonstrated increased production of detoxification enzymes either owing to exposure to xenobiotics or the body’s internal toxins. On the other hand, a sluggish clearance of caffeine is an indication of the fact that there is an abnormal activity of the enzyme cytochrome P-450 within the liver. Patients having sluggish caffeine clean up usually face problems in getting rid of xenobiotics as well as other toxic substances from the body.
Phase II detoxification
During the Phase II detoxification, different chemical groups are conjugated or added to the existing chemicals. As a result of this, the toxic chemical changes to a water-soluble compound and is eventually eliminated from the body by the kidneys. Alternatively, it is excreted through the bile when the chemical has an elevated molecular weight. Phase I detoxification is not necessary when a xenobiotic possesses a chemical cluster on the molecule from before and is appropriate for reaction during Phase II. In such instances, the xenobiotic is directly decontaminated during conjugation of chemicals in Phase II.
A number of conjugation reactions takes place during Phase II detoxification and the main ones are described briefly below.
Amino acid conjugation (also called acylation): This involves conjugation of peptide (formation of a compound when two amino acids bind by means of a special bond) employing acyl C0-A (denoting co-enzyme plus carbolic acid) as well as amino acids like glutamine, glycine, taurine and to a smaller amount, ornithine and arginine. In fact, glycine is the amino acid that is use most frequently for this purpose. Similarly, the amino acid glutamine is vital for detoxifying ammonia. This kind of union of chemicals results in the formation of hippuric acid that is sent out in the kidneys and is measurable.
Acetylation: When acetyl Co-A (denoting co-enzyme A plus acetic acid) is combined it leads to the formation of a mercapturic pair or conjugate, which is the main process for detoxifying or transforming amides (organic amalgams enclosing nitrogen) and amines. This process may be affected adversely due to an overload of pollutants as well as deficit of enzymes, irrespective of whether it is genetic or acquired.
Glucuronidation (also called gluconation): This process involves combining a sugar group, making use of glucuronic acid - the major conjunction reaction for converting xenobiotics as well as internal toxins in to metabolites that are soluble in water. This works on specific pharmaceutical drugs, dyes, derivatives of coal tar, phenols, bile salts, steroid hormones, melatonin hormones, bilirubin, estrogen as well as an overload of vitamin D, vitamin E and vitamin K.
Glutathione conjugation: Reduced glutathione merges with xenobiotics resulting in the formation of toxins that are less harmful. It has an important role in merging volatile metabolites that come into existence during the transformation of cytochrome P-450. It actually forms a major resistance against the detrimental free radicals. Glutathione conjunction is also responsible for the developing of mercapturic acid.
Methylation: This involves combining a methyl group (CH3), making use of the amino acid called methionine to provide the methyl group. Methylation helps in detoxifying several synthetic as well as internally produced toxic substances (endogenous toxins), for instance, neurotransmitters like norepinephrine, epinephrine and serotonin, in addition to various nutriments. This reaction is dependent on vitamin B6.
Sulfur conjugation (also called sulfation): This process comprises numerous reactions, counting sulfonation, which combines inorganic sulfate with hydroxyl group to enable detoxification as well as lessening cyanides by means of appending sulfur. This process helps in detoxifying accumulated food additives, drugs, steroid as well as thyroid hormones, specific contaminants present in the environment, monoamine neurotransmitters and heavy metals. This process needs additional energy compared to any other conjugation reaction and will not occur unless there is sufficient energy available.
The role of Phase II detoxification may be assessed by ingesting aspirin as well as acetaminophen. This trial helps to gauge the recovery of substances produced during glutathione conjugation, glucuronidation, glycine conjugation (also called acylation) and sulfur conjugation in the urine. Comparing the findings to the substances usually contained in the urine allows us to evaluate the effectiveness of Phase II detoxification. It is important to note that an elevated percentage between Phase I detoxification and any pathway of the Phase II detoxification means an excessive detoxification in our body.
Rates of detoxification
Any deficit of vitamins, amino acids, minerals and fatty acids has an adverse effect on the effectuality of the Phase I as well as Phase II detoxifications. For instance, consuming insufficient amounts of proteins particularly lowers clearance during Phase I detoxification, while intake of inadequate calories reduces the functioning of detoxification in general. Moreover, even foreign chemicals also have a negative effect on these detoxification processes, as the body does not have any detoxification means for them. Toxic overload owing to prolonged period of exposures to toxins, contamination of the enzymes that work to detoxify the system by heavy metals and a deficit of enzymes owing to genetic inheritance are a few examples of foreign chemicals affecting the detoxification processes.
Great quantities of caloric energy are required to continue the detoxification process. Such caloric energy is mainly derived from the foods we consume. Therefore, if we do not intake sufficient amounts of proteins, our body disintegrates the essential tissue proteins to generate the energy required to undertake the detoxification processes. When this occurs, it decreases the availability of the required amounts of Phase I as well as Phase II enzymes, peptides and amino acids, as the body disintegrates protein into peptides and amino acids. As the body’s toxic load increases, it makes it necessary that we intake more amounts of carbohydrates, fats, proteins and micronutrients.