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GUEST EDITORIAL
Year : 1977  |  Volume : 23  |  Issue : 2  |  Page : 41-49

Human metabolism of foreign compounds


Department of Pharmacology, Seth G. S. Medical College, Bombay-400 012., India

Correspondence Address:
S R Amladi
Department of Pharmacology, Seth G. S. Medical College, Bombay-400 012.
India
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Source of Support: None, Conflict of Interest: None


PMID: 614413

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How to cite this article:
Amladi S R, Valame S. Human metabolism of foreign compounds. J Postgrad Med 1977;23:41-9

How to cite this URL:
Amladi S R, Valame S. Human metabolism of foreign compounds. J Postgrad Med [serial online] 1977 [cited 2020 May 26];23:41-9. Available from: http://www.jpgmonline.com/text.asp?1977/23/2/41/42793


In the complex process of evolution, life began as an agglomeration of diverse molecules-the living protoplasm-en­closed by a membrane to form a uni­cellular organism. The unicellular orga­nism had developed in an aqueous surrounding. In order to maintain life the interior of the cell had to be kept at a constant composition, ionic strength and pH even though surrounded by a medium which was so different from the composi­tion of the cytoplasm itself. In order to continue the life process, the cell had to obtain nutrients from the environment and also had to discard unwanted end ­products of cellular metabolism. All that gained entry into the cell from the en­vironment, including nutrients, were foreign to the cell contents and hence can be called foreign substances. Even the waste products which were formed and no longer needed by the body and were actually toxic to the organism if they accumulated beyond a particular limit, may also be considered foreign com­pounds. In order to survive, the organism had to evolve mechanisms to handle those foreign substances which were useful and to discard them when they were not. Thus the process of foreign substance entering the living organism and ways and means of handling them goes far back in evolu­tion. As the cell evolved from unicellular organism in aquatic medium, through many phases to reach the present status of a most highly evolved and adaptable terrestrial animal, namely Man, these processes also became more sophisticated and diversified. With the evolution, man was not only exposed to food material and a variety of them for nutrition, but also was exposed to numerous foreign substances, many of his own making and some unavoidably from his surroundings. Drugs, food colours, cosmetic colours, food stabilizers, flavour enhancers are deliberately ingested chemicals-foreign to the organism and not exactly needed for nutrition in the strict sense, but ori­ented to make life more pleasant and more bearable. In this list can be added, substances derived from environmental pollution namely insecticides, pesticides, weed killers, chemicals from the effluents of chemical industries and exhaust gases from automobiles and the like. The list can be expanded enormously. The sub­ject assumes importance from the aca­demic point of view as to how the human body handles such a variety of substances so different in chemical composition. From the practical point of view to the sub­ject is important owing to the exposure to noxious substances which is a problem of toxicology and survival.

Sources of Exposure to Foreign Com­pounds

Pharmaceuticals : The widespread re­search in the development of new drugs for treatment of diseases, provides a major source of foreign compounds to the human body, although a few drugs contain sub­stances normally present in the body.

Industrial Chemicals: People working in chemical industries and also living around industrial areas are likely to be exposed to many chemicals like solvents, dyestuffs etc. which are readily absorbed both as liquids as well as vapours. Many of the products of oil industry are known to have widespread metabolic effects.

A whole range of chemical detergents is now available and these are used for everything from washing utensils and clothing to large scale industrial cleansing. Detergent residues remain on clothing and utensils after they have been washed, so that most people living in civilized communities are continuously exposed to low levels of detergents. This also includes the various types of bleaching and bright­ening agents.

Cosmetics: Perfumes and pigments have been used by both men and women since the dawn of recorded history. These products, at that time, were plant and animal preparations together with a few simple naturally occurring mineral sub­stances. Now there is a vast chemical in­dustry, devoted to the synthesis of new agents for use in cosmetic products like hair-dyes, lipsticks, mascara, nail polish, soaps, skin creams etc. and it is evident that very large quantities of foreign com­pounds are in everyday popular use. A high percentage of the lipstick is orally ingested, and the capacity of the skin to transfer topically applied compounds into the blood is frequently underestimated.

Food Additives: Food may be conta­minated by all manner of substances, but in recent years a wide range of synthetic chemical substances have been used on a wide scale to improve the colour, flavour or keeping qualities of food. These addi­tives represent another major source of foreign compounds in the human environment.

Pesticides: Compounds toxic to un­wanted plants insects, molluses, fungi and even mammals are all in widespread use in agriculture or in public health pro­grammes. The hazards to human beings come first from contact with relatively high concentrations of these compounds as can occur in workers in agricultural fields or persons involved in their manu­facture. Secondly, there is also an insi­dious hazard from low levels of pesti­cides throughout the human environment, Pesticides have been detected in the tis­sues of animals from nearly all places, e.g. from the polar regions, from the de­serts and also from the depth of the sea They are present in detectable quantities in human tissues from all countries and the highest amounts are present in the developed countries where their use is greatest. It is interesting to note that nearly 1000 different compounds are in use as pesticides and world usage is in excess of 1 million tons per year.

Food Anutrients: Besides the com­pound added to food like colours, flavours or contamination by pesticides, substances devoid of nutritional value called 'anu­trients' are also present in the food. The naturally occurring anutrients present in some foods include anthocyanins-which are the pigments of many fruits and vegi­tables; terpenes--which are present in the essential oils of many herbs and. fruits; methylated purines like caffeine and the like.

Then again industrial chemicals of different types may find their way into foods. Small particles of metals may be added by faulty food processing machi­nery, while fragments of wrapping mate­rial can also be present. The increasing use of plastic food containers also in­creases the chances of food contamina­tion.

Air Pollutants: People living in the areas of heavy traffic or people working in the press or in manufacture of stabiliz­ers, batteries, etc. are exposed to heavy metals like lead or mercury-which may not be metabolized in the body but their presence may interfere with the meta­bolism of other substances.

Irrespective of the route of entry, most foreign compounds are absorbed syste­mically though some are absorbed only to a limited extent. It is extremely rare for a substance to come into contact with the body without entering the blood or other tissues.

Once inside the body, almost every foreign substance is metabolized to some extent. Any compound foreign to the body is a potential poison and the out­come of the metabolism is either to break the compound into fragments which enter normal metabolic pathways, or to alter the solubility of the compound so that it is excreted more readily. Foreign com­pound metabolism (biotransformation) usually reduces the risk of toxic effects by getting rid of the compound as quick­ly as possible, although sometimes meta­bolites are formed with enhanced toxic properties.

Metabolic Transformation of Foreign Compounds

Role of The Liver: Biotransformation can occur in any of several tissues and organs. Some compounds are transform­ed chemically in the intestine, some in the lungs, the kidneys, or the skin, but the greatest number of these chemical reactions are carried out in the liver which metabolizes not only drugs but also most of the other foreign substances. Bio­transformation in the liver is therefore a critical factor not only in drug therapy but also in defending the body against the toxic effects of a wide variety of sub­stances. All the blood that has absorbed digested food and other substances from the intestines, enters the liver through the large portal vein which ramifies into fine channels through which the blood perfu­ses slowly among the liver cells. Here, nutrients and other foreign substances are removed, metabolized in some cases, stor­ed and then released into the general circulation. For example, amino acids are converted to proteins, glucose is convert­ed into glycogen and stored for conversion back into glucose whenever required. Drugs and other toxic substances are de­toxified.

The biotransformation of foreign com­pounds in the liver is accomplished by several remarkable enzyme systems which are built into the membranes of the endoplasmic reticulum of the liver cells. The endoplasmic reticulum is of two kinds-rough and smooth, and they differ both in form and function. The surface of the rough membranes are stud­ded with ribosomes, small granules that translate the genetic code into the sequen­ces of amino acids constituting proteins. The smooth membranes have no ribosomes. In the liver, the main function of both kinds of membranes is to assemble the enzymatic complexes that transform foreign substances, and then to serve as the site of those transformations.

Biotransformation is carried out by four basic reactions: (1) oxidation, (2) reduction, (3) hydrolysis and (4) conju­gation.

Oxidation, which is the central step involved is of two types-microsomal and non-microsomal.

Microsomal Oxidation: The mechanism of microsomal oxidation has been the sub­ject of much investigation, and at least the overall details are now clear. Studies with labelled oxygen have shown that the oxygen atom incorporated into the molecule of foreign compound during microsomal oxidation is derived entirely from molecular oxygen and not from water. Microsomes are known to contain cytochromes which differ from those found in mitochondria. Several different cytochromes have been described and may be involved in the oxidation of parti­cular classes of foreign compounds. Cyto chrome P-450 is the most abundant micro­somal cytochrome and is present in tissues like liver, which are actively involved in the metabolism of these compounds, but is absent from the tissues like brain which are not concerned with this type of metabolism.

The amount of cytochrome P-450 pre­sent in the liver is significantly increased following exposure to foreign compounds and this increase is abolished if actino­mycin-D, an inhibitor of messenger RNA formation, is simultaneously administered.

Like many other cytochromes, P-450 reacts with molecular oxygen to form an unstable complex. This oxygen molecule is available for foreign compounds. As only the reduced form of cytochrome P-­450 reacts with molecular oxygen, a mechanism for the continuous regenera­tion of this form is present within the microscomes. The mechanism is in many ways analogous to the electron transport pathway of the mitochondria. The process requires NADPH 2 specifically and NADH 2 is not used. The transfer of elec­trons from NADPH 2 to cytochrome P-450 is accomplished by an enzyme known as NADPH 2 - cytochrome-c-oxido-reductase and is the same enzyme present in mito­chondria. This enzyme has at least two components, a flavoprotein (FAD) and o protein containing non-haem iron. Like cytochrome P-450, the amount of the microsomal oxido-reductase also increases greatly following exposure to foreign com­pounds.

Cytochrome P-450 is present within microsomes in a protein-bound form and it is presumably the nature of protein that determines the specificity of the oxy­gen transfer reaction to the foreign com­pound. In fact these microsomal oxida­tion represent the class of enzymic re­action with the lowest degree of substrate specificity. A very large range of chemi­cally different substances get oxidised by the active form of oxidized cytochrome P-450. Phenobarbital, aminopyrine, ste­roid hormones and aromatic hydrocar­bons all appear to be oxidized by the same system.

Presence of several other microsomal cytochromes help to determine what spe­cificity there is in microsomal oxidations. Hexobarbital is oxidized by a system that will not oxidize tyramine and is true the other way. Some foreign compounds may be oxidized by two different pathways by the microsomes. If the compound is given alone, the oxidized products may be quite different from those when it is given in the presence of a second foreign com­pound. For example, when the polycyclic aromatic hydrocarbon, 7-12-dimethyl benzanthracene (DMBA) is given alone to rats the major metabolite is formed by oxidation of the 7-methyl group which has potent necrotic effects on adrenals. Now, if the rats are pretreated with some other hydrocarbon, like naphthalene or with steroids like betamethasone, these substances cause a different type of en­zyme induction than that induced by DMBA alone. If DMBA is now given, the major metabolites are ring hydroxy­lated compounds which do not cause ad­renal necrosis.

A somewhat similar effect can be seen in the interaction between certain drug: and the metabolism of endogenous steroid hormones. Phenobarbitone has beer Lund to increase the rate of turnover of several steroids including cortisol and testosterone.

Non-microsomal Oxidation: While the microsomes are the most important sub cellular fractions involved in the metabolism of foreign compounds, a number of reactions also occur catalysed by soluble enzymes of the cell sap. An important nonmicrosomal enzyme is alcohol dehydrogenase which catalyses the rever­sible inter-conversion of primary alcohols and aldehydes. Another important soluble enzyme is aldehyde dehydrogenase which catalyses the conversion of primary alde­hydes to the corresponding carboxylic acids.

Oxidation accounts for most of the metabolic transformations. The alkyl side-chains of barbiturates and some other drugs are oxidized to form alcohols. In the case of compounds incorporating aro­matic rings including polycyclic hydro­carbons, for example in cigarette smoke and many drugs, a hydroxyl group is inserted into the ring. In other cases; alkyl groups are removed from either nitrogen or oxygen atoms, amino groups are removed or sulfoxides are formed.

Reduction and hydrolysis are also cata­lysed by liver enzymes but these reac­tions are less common. Prontosil and sul­fanilamide are metabolized by reduction and procaine by hydrolysis.

Conjugation of a chemical is combina­tion with some natural constituent of the body, such as the glucose derivative-­glucuronic acid, the amino acid glycine or the tripeptide glutathione. In the pre­sence of the appropriate enzyme, these natural agents can combine readily with compounds that have carboxyl (COOH), sulfhydryl (SH), amino (NH 2 ) or hy­droxyl (OH) groups. Some compounds like benzoic acid have these groups in their active form and are handled in the liver by conjugation. However, for most drugs, conjugation is a second step after metabolism by the other methods.

The mechanisms of conjugate forma­tion, differ for each chemical class. For glucuronates, the conjugate is formed by a transfer of a glucuronic acid residue from uridine diphosphate (UDP) glucu­ronate to the foreign compound, a re­action catalysed by microsomal UDP-­trans-glucuronidase.

The other major class of conjugates are the sulphates, which are formed by the transfer of the sulphate group from (3) ­phosphoadenosine -(5)- phosphosulphate (PAPS). This is formed in 2 steps by interaction between ATP and SO 4 . [ATP + SO 4 ATP sulphate-adenyltransferase Adeno­sine-(5)-Phosphosulphate (APS); ATP + APS ATP. APS. Phosphotransferase PAPS +ADP]. The sulphate group from PAPS in thereafter transferred to the foreign molecule, a reaction catalysed by the soluble enzyme sulphotransferase.

Conjugation with amino acids or their derivatives is an important mechanism for only a small group of foreign com­pounds such as aromatic carboxylic acids.

For glycine or glutamine, the conjuga­tion mechanism is indirect. A coenzyme-A derivative of the foreign compound is first formed, this then reacts with the amino acid to form a peptide like bond, while the coenzyme A is released.

Glutathione conjugates are formed mainly with aromatic hydrocarbons and are known as mercapturic acids.

Examples of Drug Metabolism

With this outline of general principles of mechanisms of metabolism, some examples of biotransformation of different classes of chemical compounds are con­sidered to illustrate the reactions involved and the products formed.

Salicylates: All commonly used esters of salicylic acid are hydrolysed within the body to release the free acid. This then undergoes microsomal oxidation to form gentisic acid and trihydroxybenzoic acid, both of which appear in the urine, together with salicylic acid mainly as the glucuronide. 20% of salicylate is meta­bolized and excreted in this way and the remaining 80% is metabolized to the gly­cine conjugate-salicyluric acid.

Phenothiazine Tranquillizers: More than 30 individual metabolites of chlor­promazine appear in the urine. Thiorida zine and imipramine are metabolised in a similar way but the structural differen­ces alter the pattern. Thioridazine has 2 sulphur atoms, both of which can undergo oxidation to the corresponding sulfoxides or even the sulphone in the case of the S in the side chain. In Imipramine which lacks an S-atom the ethylene bridge can be hydroxylated on either carbon. Oxi­dation of the N-side chain gives mono­and di-demethylated derivatives so that the range of metabolites in human beings is analogous to those for CPZ.

Barbiturates: Chemically three types of processes can be recognized in metabolism of the barbiturates: ring scission, oxida­tion and addition or removal of substi­tuents.

Industrial Chemicals: Benzene is wide­ly used in many industries but is among the most difficult of foreign compounds for the human body to detoxify. It pre­sents a uniformly hydrophobic molecule with no substituent or grouping that may be acted upon by enzymes. A small amount is metabolized by the body in a variety of ways, but it is a very toxic compound, difficult to remove from tis­sues, and may eventually induce aplastic anaemia and liver damage. The principal metabolite is phenol which is excreted in urine both as the glucuronate and sul­phate. In contrast to benzene, toluene (methyl benzene), is much less toxic and about 80% is rapidly excreted in urine as hippuric acid, the remaining being excreted unchanged via the lungs. As ring hydroxylation does not occur phenols are not formed. Oxidation of the methyl group to yield benzoic acid takes place through the intermediates benzoyl alcohol and benzaldehyde.

Xylol, which is a mixture of three iso­meric dimethyl benzenes, is extensively metabolised to corresponding toluic acids which are excreted in urine as glycine and glucuronide conjugates.

Naphthalene is widely used in many industries and has been shown to be cap­able of inducing cataract. This toxic action is due to its metabolite 1-2-dihydroxy­naphthalene, which is formed via its 1-2 epoxide.

Tetralin (tetrahydronaphthalene), which is widely used in polishes and paints as a turpentine substitute, is readily metabolised by hydroxylation of the saturated ring to α-tetralol and β-tetralol.

Like benzene, chlorinated aliphatic hydrocarbons, present a difficult metabo­lic problem to body tissues. Over 80%, of the dose of carbontetrachloride and over 90%, of chloroform or tetrachlorethylene, appear unchanged in expired air. Toxic actions, particularly on liver, of all these compounds are well known. About 1% of carbontetrachloride and 4% of chloro­form are converted to CO 2 , presumably through reductive dechlorination and then oxidation.

Dyestuffs: Some drugs and dyes con­tain aromatic amines which are known to be associated with bladder cancer. The simplest compound is aniline (aminoben­zene) which is largely excreted in urine as conjugates of various aminophenols. The most abundant metabolite is p-amino­phenols. α-naphthyl amine is similarly metabolised with the principal metabolite in the urine being conjugates of 1-amino, 2-naphthol and 1-amino, 4 naphthol.

Neither aniline nor α-naphthylamine have been proved carcinogenic in con­trast to β-naphthylamine where the evi­dence is conclusive. Interestingly, meta­bolites of β-naphthylamine are different from those of aniline or α-naphthylamine. Ring hydroxylation of β-naphthylamine produces a mixture of 2-amino-6-naph­thol and 2-amino-l-naphthol which ap­pear to be bladder carcinogens. Some transformations of compounds may occur in vitro into toxic agents during food pro­cessing. Many amines present in meat are demonstrated to combine with nitrites and colourants to form nitrosamines which cause colonic and bladder cancers; this is more common when meat is smoked or prepared on live coals.

Many dyes are used in cosmetics and food colourants. The azo dyes are acted upon by a liver reductase which catalyses their conversion to a mixture of amines, but this enzyme is of low activity and probably most dye metabolism is con­ducted by gastrointestinal micro-orga­nisms.

Chrysoidine, also known as `Orange II', is extensively metabolised. Reduction of the azo group yields one molecule of 1-amino-2-naphthol and one of sul­phonic acid. The latter compound is partly acetylated to p-acetamidobenzene sulpho­nic acid and partly excreted unchanged; 1-amino-2-naphthol is conjugated with glucuronate and sulphate.

About 1% of `Sudan 1' is excreted unchanged but the principal metabolite is p-aminophenol, which is formed partly from aniline released by reduction of the amino group, and partly by p-hydroxyla­tion of the benzene ring prior to reduc­tion.

Besides the dyes, sweetening agents like cyclamates or saccharin are some­times added to foods. Both of them are rapidly excreted unchanged in the urine. No metabolites of saccharin have been de­tected so far, while in a few persons cyc­lohexylamine is detected as a metabolite of cyclamate. Cyclohexylamine is a puta­tive carcinogen, therefore, the use of cyc­lamate is officially not sanctioned.

Benzoic acid is used as a preservative. It is conjugated with glycine to form hip­puric acid and is excreted almost entirely. Para-alkyl-benzoic acid derivatives or its various esters are also widely used as preservatives and are rapidly hydrolysed in the body.

Aside from naturally occurring tocophe­rols, the commonest food anti-oxidants are butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). BHA is a mixture of 2- and 3- tert-butyl 4-hy­droxyanisole and it is metabolised to its glucuronate form. In contrast, BHT gives rise to large series of metabolites, as the hydroxyl group is sterically hindered by the tert-butyl groups and cannot form conjugates.

Pesticides: Large amounts of phenoxy­acetic acids are used as herbicides, which are strong, water soluble acids and are rapidly eliminated.

DDT is used most widely as an in­secticide. It is fat soluble and metabolised very poorly by humans. Consequently, ingested DDT is absorbed with dietary lipids and deposited largely unchanged in adipose tissues. Two metabolic path­ways operate in humans. The first is a reductive dechlorination to the corres­ponding dichloro-ethane (DDD) which then undergoes hydrolytic dechlorination and oxidation to a carboxylic acid (DDA) which is conjugated with the amino acids serine and aspartic acid. The second path­way is an oxidative dechlorination to yield dichloroethylene (DDE) which is a major metabolite in adipose tissue.

Aldrin and dialdrin differ only by an epoxide group, which can be added to aldrin by metabolism. The reaction is difficult and aldrin is largely unmetabo­lised. Dialdrin is metabolised by opening the epoxide to the corresponding dihy­droxy derivative; several other metabo­lites have also been detected.

Organophosphorus insecticides, para­thion and malathion, are readily metabo­lised in vivo to paraoxon and maloxon. Both of these metabolites are potent anti­cholinesterases-an example of lethal synthesis. Further metabolism of para­thion yields diethyl phosphate and p­-nitrophenol, which is reduced to p-amino­phenol and excreted in urine.

Like organophosphorus compounds carbamate insecticides act as anticholine­sterases, but do not require metabolic acti­vation. All the metabolites are less active than the parent compounds. Most com­pounds in this series are aromatic carba­mates and are subject to microsomal oxi­dation.

Food Anutrients: Many anutrients of plant foods occur as glycosides and ex­tensive hydrolysis occurs by intestinal bacteria, to release aglycones. The extent of further metabolism depends on the particular substance. Oily compounds like terpenes, may be metabolised by enzymes of important metabolic pathways, such as fatty acid B-oxidation. Methyl purines like caffeine are subjected to demethyla­tion and then excreted in urine as mono­or dimethyl-uric acids.

Metabolism in Neonates

So far as the neonatal metabolism is concerned, the presence of metabolites in the urine gives evidence that infants have an active enzyme system and cytochrome P-450 for carrying out aliphatic and aro­matic hydroxylations and allylic and aro­matic epoxidations from the first day, for example the metabolites dihydroxy seco­barbital and dihydrodiol of dilantin have been detected.

Caffeine is excreted unchanged in the urine of neonates, suggesting that the rate of N-demethylation is much slower in the infant than in mother.

Though there is evidence that the meta­bolising enzyme system is present in the neonate, the rate of metabolism is very slow and that causes the prolonged action of active drugs, and this may be impor­tant from the toxicological point of view. However, the glucuronate conjugating mechanism is not well developed in infants upto 3 months of age.

Interactions between foreign compounds in the body

Patients are often given several drugs at the same time. Certain combinations can have unpredictable and sometimes undesirable effects if one drug inhibits or stimulates the metabolism of another or competes with it. For example, phenyl­butazone and chloramphenicol compete with the metabolic inactivation of tolbu­tamide, which can lead to excessive tol­butamide activity causing serious hypo­glycemia.

Enzyme induction with phenobarbitone is well known and sudden withdrawal causes toxicity of other drugs given con­comitantly like phenylbutazone, antipyrine, coumarin, anticoagulants, etc.

Heavy alcohol drinkers are found to have an increased concentration of cyto­chrome P-450 and therefore stimulate the metabolism of a wide variety of drugs.

Besides drug interactions, the ability of environmental pollutants to modify drug action is now under active investi­gation. It is clear that insecticides stimu­late drug metabolising enzymes and heavy metals like lead and methyl mer­cury inhibit the enzymes.

The process of metabolism is complex and many enzymes are involved in it. II due to some genetic defect a particular enzyme is absent, it will affect the meta­bolism of certain substances; for example succinylcholine is rapidly inactivated it normal people by cholinesterase of lives and plasma. In a small number of people who lack this enzyme, succinylcholine is metabolised very slowly and they may develop prolonged muscular paralysis and apnoea. Isoniazid is another example Some individuals metabolise it rapidly and some very slowly depending upon the ability of the liver to produce acetylco­enzyme-A.

It is indeed fascinating how the human organism is capable of handling such a vast spectrum of chemical agents. The metabolism of numerous foreign sub­stances has not been fully explored, and as more and more new compounds come into existence the metabolic load on human beings will increase, as also considerations of benefit versus risk pro­duced by them. The use of sophisticated methods like gas chromatography, espe­cially that coupled to mass spectrometry with computerisation have opened up new avenues in understanding metabolism of chemicals. However, what is undoubt­edly most important to those concerned with human welfare is to be aware of the problems posed by exposure of the population to foreign compounds.






 

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Online since 12th February '04
© 2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
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