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Introduction to Detoxification
This Sqadia video is the elucidation of Detoxification. The term detoxification means that all the biochemical processes, whereby noxious substances are rendered less harmful and are more easily excreted in urine. Several theories explain detoxification. Theory of Sherwin states that detoxication mechanisms render so called toxic compounds less toxic by transforming them into more soluble derivatives, which are then more easily excreted. Theory of Berczeller proposed that toxic compounds are made less toxic by transformation into compounds having a surface tension nearly like water than the parent compound. Theory of Quick proposed that the important factor is conversion of a weakly acidic substance to a strongly acidic one. By definition the term detoxication covers all those biochemical changes proceeding in the body, which convert foreign molecules, generally toxic, but not always so, to generally non-toxic or less toxic but not always so, and more soluble so that they can be easily excreted. Foreign molecules may be Exogenous, and some may be Endogenous. Foreign molecules, which enter the body are called xenobiotics. There are mainly four types of detoxication mechanisms: Oxidation, Reduction, Hydrolysis, and Conjugation. In man, detoxication is principally carried out in liver, but to some extent it can be carried out in kidneys also. Present concept is that the reactions of xenobiotics occur in two phases. Phase 1 involves the hydroxylation, the major reaction, catalysed by mono-oxygenases or cytochrome P450 species. In Phase 2 the hydroxylated or other compounds produced in phase 1 are converted by specific enzymes to various water soluble polar metabolites by conjugation.
A large number of foreign substances are destroyed in the body by oxidation. Aliphatic as well as aromatic alcohols may be oxidised to corresponding acids, probably via aldehyde formation. In addition, certain amines, anilides and drugs also can undergo oxidation. Methyl Groups can be oxidized to form – COOH group through formation of aldehyde. Aromatic hydrocarbons are oxidized to Phenol and other phenolic compounds. Anilides are oxidised to the corresponding Phenols i.e. p-acetyl amino phenol. The sulphur present in organic sulphur compounds is oxidised to SO4, which in turn may be excreted in inorganic or organic form or as neutral sulphur. Certain drugs can be oxidised in the body and are excreted as hydroxy derivative or salts e.g Meprobamate and Chloral.
Reduction and Hydrolysis
Reduction usually does not occur extensively in man. Certain aldehydes, e.g. chloral, a hypnotic, principally undergoes reduction in the body to form corresponding alcohol, which is then conjugated with D-glucuronic acid and excreted as corresponding glucuronides. Aromatic nitrocompounds, e.g. p-nitrobenzaldehyde is reduced to corresponding amines and excreted after conjugation. There are quite a number of therapeutic compounds, used as drugs, which undergo hydrolysis, usually in liver. For example, Acetyl salicylic acid reduces to Acetic acid and Salicylic acid (Aspirin). Salicylic acid can reduce Benedict’s Qualitative reagent.
Conjugation is a process by which the foreign molecules or its metabolites are coupled with a conjugating agent and converted to soluble, nontoxic derivatives which are easily excreted in urine. Various conjugating agents are available in the body and some of them are synthesised in the body, e.g. D-glucuronic acid formed from glucose by uronic acid pathway. A detoxication process though limited in the body, at the same time is quite important. Usual methyl donor is “s-adenosyl methionine”. Methylation of heterocyclic n-atom of compounds of the pyrimidine and quinoline types, e.g. Nicotinamide. This occurs also with other heterocyclic aromatic compounds, e.g Histamine. In detoxication reactions, conjugation with acetic acid occurs only with aromatic NH2 group. In humans, certain drugs, e.g. sulpha drugs are conjugated by acetylation. The drug “Isoniazid”, used in treatment of TB is detoxicated by acetylation. Polymorphic types of acetyl transferases exist, resulting in individuals who are classified as Slow Acetylator and Fast Acetylator. Sulphuric acid is used by human beings for detoxication of various compounds having phenolic or hydroxyl groups. “Active” sulphate acts as the donor, chemically it is 3’-phosphoadenosine-5’-phosphosulfate (PAPS). In the process of conjugation, the glucuronic acid can form two types of linkages: An “ether” linkage and an “ester” linkage. Glycine combines with potentially harmful substances, mainly aromatic carboxylic acids in the body to form harmless derivatives which are excreted in urine.
Types of Conjugation
In man and in primates, glutamine conjugates phenyl acetic acid to form ‘phenylacetyl glutamine’ and excreted in urine. This accounts for “mousy” odour of urine in phenyl ketonurics. Animals normally excretes thiocyanates which is non-toxic. Cyanides are conjugated by “thiosulphates” or even in presence of colloidal sulphur. The reaction takes place in the liver and is catalysed by the enzyme thiosulphate cyanide sulphur transferase. Several potentially toxic electrophilic xenobiotics, e.g. certain carcinogens are conjugated to the nucleophilic G-SH. The reaction is catalysed by the enzyme glutathioneS-Transferases. If the potentially toxic xenobiotics are not conjugated with G-SH, they would be free to combine covalently with DNA, RNA or cell proteins and can produce serious cell damage. Most of the drugs more than 50 per cent are detoxicated by hydroxylation. Selenium poisoning develops due to high feeding of products obtained from the soil having high contents of selenium. It can be cured by administering p-bromobenzene. It is also known as 2,3-mercaptopropanol or “BAL” (British-anti-Lewesite). ‘BAL’ was used as a detoxicant for certain war poisons. Exact mechanism of action is not known. Toxic metal ions combine with –SH groups of body enzymes or other important –SH groups containing molecules and thus inactivate them. Recently another cytochrome P450 species has been found called as cytochrome P448. It has been found to be very important enzyme for metabolism of PAHs and in carcinogenesis produced by these agents. Some reports have shown that activity of this enzyme is increased in placentae of pregnant women who are cigarette smokers and thus foetus is exposed to potentially harmful metabolites.