The liver is the 2nd largest secretory organ in the organic structure, weighing between 1 and 3 kilogram. It is located in the upper portion of the abdominal pit busying the greater portion of the right hypochondriac part, portion of the epigastric part and widening in to the left hypochondriac part. Its upper and anterior surfaces are smooth and curved to suit the under surface of the stop. Its posterior surfaces are irregular in out line. The liver is enclosed in a thin elastic capsule and incompletely covered by a bed of peritoneum. The liver consists of two anatomical lobes.
1. Right lobe
2. Left lobe.
The right lobe being about six times greater, so the size of the left lobe. The right lobe has quadrate lobe on its inferior surface and a caudate lobe on the posterior surface. The right and left lobes are separated anteriorly by a crease of peritoneum called the falciform ligament, inferiorly by the crevice for the ligament tares, and posterior by the crevice for the ligament venosum. The liver is particular in that it can regrow its ain tissue. Equally much as three-fourthss of the liver can be removed, and the organ can turn back in about a month. Because of this regrowth, liver for graft can be taken from populating givers. ( Ross and Wilson, 2006 ) .
The hepatic arteria and the portal vena supply the blood to the liver. Venous return is by a variable figure of hepatic venas that leave the posterior surface and instantly come in the inferior vein cava merely below the stop. Liver lobules are hexangular in lineation and are formed by cubelike molded cells, the hepatocytes arranged in braces of columns radiating from a cardinal vena. Between two braces of columns of cells are sinusoids ( blood vas with uncomplete walls ) incorporating a mixture of blood from the bantam subdivisions of the portal vena and hepatic arteria.This agreement allows the arterial blood and portal venous blood to blend and come in to shut contact with the liver cells. Amongst the cells run alonging the sinusoids are hepatic macrophages ( kupffer cells ) whose map is to consume and destruct worm out blood cells and foreign atoms present in the blood fluxing through the liver.
FUNCTION OF LIVER
The liver ‘s occupation is to run over 500 bodily maps. It plays a function in the processing of metamorphosis and elimination of xenobiotics from the organic structure. It besides plays a cardinal function in the organic structure ‘s defence system. It processes about everything a individual chows, breathes, or takes in through the tegument. About 90 % of the organic structure ‘s foods pass through the liver from the little and big bowels.
The liver changes nutrient into energy shops this energy is used for the production of blood proteins. The livers besides detoxify the bacteriums and toxicants from the blood. A babe ‘s liver besides makes blood cells in the uterus. ( Ross and Wilson, 2006 )
ROLE IN DIGESTION
The liver plays an of import function in the dislocation of nutrient in the organic structure. Liver cells make gall, a greenish-yellow fluid that helps in the dislocation of fats and in conveying foods into the organic structure. Waste made by the liver in the dislocation of nutrient is carried in the gall and excrete from the organic structure through the kidney. Person with a liver that is non working decently those may hold less bile production. They may non treat the elimination of wastes as compared to a individual with a healthy liver. When this happens, the organic structure may hold problem in treating nutrient and other chemical substances. Liver cells besides convert haem ( a part of haemoglobin that is released when ruddy blood cells are broken down ) into Bilirubin. When the liver is damaged, Bilirubin may construct up in the blood doing yellowing of the tegument and Whites of the eyes ( icterus ) .
METABOLISM IN LIVER
The liver helps to supply the energy to the organic structure by the procedure of metamorphosis. It controls the production, storage, and release of sugar, fats, and cholesterin. When nutrient is taken, the liver alterations glucose ( blood sugar ) into animal starch. The animal starch is so stored in the liver as an energy beginning for later usage. The liver changes animal starch back into glucose when energy is needed at dark. This procedure is called glucogenolysis. The liver controls the storage of fats by altering aminic acids ( the edifice blocks of protein ) into fatty acids. Some fatty acids, such as triglycerides are changed by the liver into ketones. Ketones are fuel for musculuss. Ketones are used when the organic structure does non hold adequate sugar. The liver besides makes procedures and removes cholesterol from the organic structure. Cholesterol is an of import portion of cell constructions and certain endocrines ( Harsha Mohan, 2010 ) .
Though the liver has a marked regenerative capacity and a big functional modesty Hepatic failure may develop from terrible ague and fulminant liver hurt with monolithic mortification of liver cells ( acute hepatic failure ) or from progresss chronic liver disease ( chronic hepatic disease ) . Acute liver failure develops all of a sudden with terrible damage of the liver map where as chronic liver failure comes perniciously. Liver hurt or liver disfunction is a major wellness job that challenges non merely wellness attention professionals but besides pharmaceutical industry and drug regulative bureaus.
There are two types of the hepatic failure consequence from different causes.
Acute ( fulminant ) hepatic failure:
It happens largely in terrible viral hepatitis. Other causes are hepatotoxic drug reactions ( Anaesthetic agents, NSAIDS, Anti sedatives ) , CCl4 toxic condition, acute alcoholic hepatitis, mushroom toxic condition, and gestation complicated with eclampsia.
Chronic hepatic failure:
It is the most common due to the cirrhosis. Other cause includes chronic active hepatitis, chronic acholia & A ; Wilson disease.
The diverse maps performed by the liver, the disease of ague or chronic hepatic failure produces complex manifestations. The major manifestations are as follows.
( Harsha Mohan ) .
Hepatic brain disorder ( hepatic coma )
Hepato nephritic syndrome
Hepato pneumonic syndrome
Ascitess and hydrops
Skin alterations and
Toxic liver hurt produced by drugs and chemicals may virtually mime any signifier of of course happening liver disease. Hepatotoxicity from drugs and chemicals is the commonest signifier of iatrogenic disease. Badness of the hepatotoxicity is greatly increased if the drug is continued after symptoms develop.
Among the assorted inorganic compounds bring forthing hepatotoxicity are arsenic, P, Cu and Fe. The organic compounds include certain of course happening works toxins such as pyrrolizidines alkaloids, mycotoxins and bacterial toxins. The man-made group of the organic compounds is a big figure of medicative agents. In add-on exposure to hepatic compounds may be occupational, environmental or domestic that could be inadvertent, murderous or self-destructive consumption.
Drug reactions impacting the liver are divided in to two chief categories.
Direct or predictable:
When the drug or one of its metabolite is either straight toxic to the liver it lowers the host immune defence mechanism. The inauspicious effects occur in most persons who consume them and their hepatotoxicity is dose dependant.
Examples: C tetrachloride
Indirect or unpredictable or idiosyncratic:
When the drug or one of its metabolites act as a hapten and induces hypersensitivity in the host. The hepatotoxicity by this group does non happen on a regular basis in all the persons and the effects are normally non dose related. ( Harsha Mohan ) .
Symptoms of hepatotoxicity
Loss of appetency
Enlarged liver, Etcaˆ¦
Drug INDUCED HEPATOTOXICITY
The most widely prescribed curative drugs have been focused attending on the hepatic safety of drugs. A important figure of drugs has been proven, or at least suggested, to do hepatotoxicity. There are 900-1000 drugs and chemical substances are doing the liver toxicity throughout the universe broad. It must be recognized that a drug is a chemical or biologic agent that has been found to do a therapeutically action on a symptom or disease procedure, has been tested or identified for safety, and so if approved, is widely available for diagnostic intent. There are many clinical diagnostic centres has given the manifestations, which specially suggest that a liver toxicity is the consequence of a curative drug, with a dose dependent mode. The most of import 1 is frequently the temporal relationship between induction of a drug and the presence of the hurt and of equal importance is the declaration of an abnormalcy following backdown. The attending has been given to the universe population for the recognization of factors, which doing the harmful effects to the liver and who are increased the hazard of developing hepatic harm from figure of drugs and chemical compound ( Willis C.Maddrey, MD 2005 ) .
SPECTRUM OF HEPATOTOXICITY INDUCED BY DRUGS
The spectrum of drug induced liver hurt get downing from initial, nonspecific important alterations in the biochemical parametric quantities of no clinical effects to acute hepatitis, chronic hepatitis, acute liver harm, chronic cholestatic disease and even cirrhosis and liver tumours.
Drugs withdrawn or badly limited because of hepatotoxicity.
PREDICTIVE PARAMETERS OF DRUG-INDUCED LIVER DAMAGE
There are comparatively few ways by which ague and chronic liver diseases become clinically important. The features of drugs and chemicals induced liver disease are by and large nonspecific and reflect more the extent of the liver hurt than the cause. The marks and symptoms found in many hepatic diseases such as acute viral hepatitis, chronic viral hepatitis, or chronic acholia diseases.
Factor THAT INFLUENCING SUSCEPTIBILITY TO DRUG-INDUCED LIVER DISEASE
Age, sex and the uninterrupted usage of other medicines are of import factors to see in measuring an single patient ‘s susceptibleness to drug induced liver disease. There are few agents, among them Valproic acid and erythromycin estolate, which preponderantly cause inauspicious hepatic reactions in kids. Valproic acid-induced liver toxicity is besides more prevailing in patients who have inherited mitochondrial upsets. For most of drugs females are at an increased hazard of developing an inauspicious hepatic reaction, when compared with that found in males.
MECHANISM OF HEPATOTOXICITY
Several mechanisms have been suggested that, most of the drugs and chemical compounds have been involved in bring forthing drug induced liver toxicity. The chemical or drug which bring forthing the liver toxicity is referred as the hepatotoxins. Some therapeutically of import drugs are produced hepatotoxins and are readily identified as such in presymptomatic and clinical ratings. With many drugs intermediary merchandises produced during metamorphosis have been proved to be extremely reactive and toxic. Potentially toxic metabolic merchandises may be present merely transiently and are quickly metabolized farther into harmless substances, thereby avoiding hurt. The cytochrome P450s, a household of enzymes mostly involved in initial oxidative ( phase I ) reactions of drug metamorphosis, has established functions in the production of extremely reactive intermediates every bit good as established functions in farther metamorphosis and accretion. Designation and word picture of the assorted cytochrome P450 races involved in metamorphosis of a drug allow anticipations to be made sing the likeliness of production of reactive intermediates and may concentrate appraisal of the possible for drug-drug interactions, if two or more drugs are used in combination. For a turning figure of drugs, there is grounds that familial polymorphism in metabolic tracts are of import in finding which persons are likely to hold an inauspicious reaction.
Specific DRUGS OF SPECIAL Interest
Paracetanol-induced hepatic hurt is the most common signifier of drug-induced liver harm and more peculiarly of ague liver toxicity in the United States, accounting for about 50 % of all instances. Paracetanol is likely the most widely used drug in the United States and is found in a singular figure of prescribed and nonprescription individual and combination merchandises, including cold redresss and medicines for hurting ( Vicodin ) with names that in no manner indicate paracetamol is a constituent. Paracetanol is established dose-related hepatotoxins. In healthy persons, there is seemingly a considerable curative scope between harmless and harmful doses of paracetamol. In curative doses ( 3 g/day ) , the drug is normally rather safe and good tolerated. Consumption of inordinate sums of paracetamol ( 10-15 g ) , frequently in self-destructive efforts, predictably leads to liver hurt and on occasion decease. The issues lie in measuring the hazard of patients having paracetamol of 3 to 10 g/day, and whether there are scenes in which liver hurt is more likely to happen when the patient has non taken a big sum of the drug with a self-destructive purpose ( alleged “ curative mishaps ” ) Hepatic hurt from paracetamol is caused by the effects of a extremely reactive metabolic merchandise, N-acetylbenzoquinone-imide ( NAPQI ) . Paracetanol is preponderantly metabolized by junction reactions to organize sulphate and glucuronide metabolites, which are excreted in the piss. A lesser sum of the drug is metabolized by cytochrome P450 2E1 to organize N-acetylbenzoquinone-imide, Which is quickly bound to intracellular glutathione and excreted in the piss as mercapturic acid, When inordinate sums of paracetamol are ingested, the ability to conjugate is overwhelmed and metamorphosis by cytochrome P450 2E1 becomes of much greater importance. In these state of affairss, the capacity of glutathione to function as an effectual hepatoprotectant may be overwhelmed, and the hepatocyte becomes comparatively defenceless against onslaught by the reactive intermediates. Two of import factors determine the production of hepatic hurt by paracetamol, the sum of N-acetylbenzoquinone-imide produced by P450 2E1 and the handiness of glutathione as a hepatoprotectant. The intracellular concentration of NAPQI and dosage of paracetamol ingested are clearly associated. However, there is more to the narrative than merely dosage. Factors that affect the production of cytochrome P450 2E1 and of glutathione are of importance. With chronic consumption of intoxicant, doses of paracetamol near or even with the suggested curative scope may take to liver hurt, promoted by an alcohol-induced lessening in intracellular glutathione and perchance an addition ( existent or comparative to GSH ) of cytochrome P450 2E1. The terminal consequence is overrun of NAPQ1 relation to the dispositional tract of GSH taking to a heightened likeliness of liver harm. It must be noted that there continues to be controversy sing the hazard of paracetamol usage in patients who drink intoxicant. Many treatments have occurred at the U.S. Food and Drug Administration sing labeling and the demand for increased consciousness of hazards by the populace. There is general understanding that an overdose of paracetamol is more likely to do liver hurt in a patient who is a chronic alky. The argument is the definition of overdose and the sum of intoxicant consumption needed to predispose the patient to injury. N-acetylcysteine, now available in both unwritten and endovenous preparations, has proven effectual when given early in the class of minimising paracetamol-induced hurt
The kidneys are the bean shaped mated variety meats, each weighing about 150 the grownup male and about 1 the grownup female. The hilus of the kidney is located at the center on the median facet where the arteria, vena, lymphatics and ureter are located. The kidney is surrounded by a thin hempen capsule which is disciple at the hilus.
Cut surface of the kidney shows three chief constructions good demarcated
Peripheral cerebral mantle
Inner most nephritic pelvic girdle.
The nephritic cerebral mantle forms the outer rim of the kidney and is approximately 1cm in thickness. It contains all the glomerular and about 85 % of the uriniferous tubule tubules, staying 15 % uriniferous tubules dwelling of roll uping tubules, roll uping canals, cringle of the henle and vasarecta send their cringles in to the myelin, and are hence called Juxtamedullary uriniferous tubules.
The nephritic myelin is composed of 8-18 cone shaped nephritic pyramids. The base of a nephritic pyramid lies next to the outer cerebral mantle and forms the cortico-medullary junction ; while the vertex of each called the nephritic papilla contains the gap of each nephritic pyramid for transition of urine collected from roll uping canals and goes down in to minor calyces.The nephritic pelvic girdle is the funnel shaped aggregation country of the piss for drainage in to the ureter.
FUNCTIONS OF THE KIDNEY
In general the kidney performs the undermentioned critical maps in the organic structure.
Elimination of waste merchandises ensuing from protein metamorphosis
Regulation of the acid-base balance by elimination of H+ ions ( acidification ) and bicarbonate ions.
Regulation of salt H2O balance by endocrines secreted both intra and excess renally.
Formation of renin and erythropoietin and there by playing a function in the ordinance of the blood force per unit area and erythropoietin severally. ( Ross and willson ) .
PATHOPHYSIOLOGY OF RENAL DISEASE
Diseases of the kidney are divided in to 4 major groups harmonizing to the prevailing engagement of the corresponding structural constituents.
Nephritic failure is one of the major complications of myeloma, found at presentation in 20 % of patients and happening in 50 % of patients during the cause of disease. Merely 20 % of the grownups with a nephritic syndrome have minimum alteration kidney disease and for that ground a nephritic biopsy is necessary to set up the type of glomerulonephritis. Idiopathic glomerulonephritis histories for 90 % of childhood instances of nephritic syndrome and 80 % in grownup patients. In patients showing with acute nephritic failure the proportion with acute interstitial Bright’s disease varies from 6.5-1.5 % . A recent twelvemonth survey ( 2000 ) from nephritic units and ICU in a defined geographical country of Scotland found that 131 patients per million per twelvemonth required nephritic replacing therapy for acute nephritic failure.
The incidence of chronic kidney disease taking to dialysis varies worldwide: the figure of patients per million population get downing dialysis each twelvemonth is 110 in the UK.
In acute nephritic failure causes untold agony among patients taking to complications that sometimes lead to decease It is estimated that in India, there are estimated 80, 000 people with terrible nephritic failure. About 15 per centum of diabetics succumb to some nephritic complication or nephritic failure
In India, the Chandigarh survey showed that 30 old ages ago diarroheal disease and obstetric complications each accounted for about 25 % of instances of ARF in north India but more late each has accounted for approximately 10 % .
Intravascular hemolysis is a common characteristic of many instances, being found in over 20 % of 325 patients having dialysis for ARF in Chandigarh. ARF develops in 5- 30 % of the victims of terrible serpent viper toxic condition and is the cause of between 2-3 % of instances of ARF. In Europe nephritic biopsy, performed for the indicant of unexemplified acute nephritic damage, shows interstitial Bright’s disease ( Harsha Mohan ) .
Water and Na homeostasis and their upsets
Entire organic structure H2O histories for approximately 60 % of the organic structure weight of a healthy grownup: two tierce is intracellular and one- tierce is extracellular. The extracellular fluid compartment is divided into vascular ( blood volume ) and interstitial fluid compartments in the ratio 1:2 for a 75kg grownup, the entire volume of organic structure H2O is about 45 litres, with intracellular and extracellular volumes of 30 and 15 litres severally, the subsequently consisting the blood ( 5 litres ) and interstitial ( 10 litres ) compartments. Sodium is the chief intracellular cation, which with its anion chloride contributes 95 per centum of the extracellular solute. By contrast the major intracellular cation is potassium. Many cell membranes are freely permeable to H2O, but non to most electrolyte, which consequences in the extracellular and intracellular compartments.
Body H2O and hence solute concentrations are regulated chiefly by antidiuretic hormone ( ADH ) mediated change of nephritic H2O elimination, but besides to some extent by thirst as a motive for imbibing. The secernment of antidiuretic hormone and thirst are influenced chiefly by alterations in go arounding concentration of Na, but besides in past by important falls in blood volume or force per unit area. The volume of extracellular compartments is determined by its entire Na content, which is regulated by legion mechanisms. Sodium consumption is ill controlled in worlds, although some animate beings do demonstrated a specific Na appetency. The kidney is the major effecter organ act uponing sodium homeostasis.
Complex intrarenal mechanisms contribute to the care of Na homeostasis, in add-on to which are endocrinal factors that either tend to cut down elimination of Na by the kidney for illustration renin-angitensin-aldosterone system or which produce a natriursis. Blood volume and force per unit area are besides influenced by a assortment of vasaoactive substances that act locally or systemically ( ex: catecholamines, prostaglandins, azotic oxide, Endothelin ) . It can hence be appreciated that there is an intricate web of homeostatic mechanisms commanding both Na and H2O balance.
Disorders of H2O and salt homeostasis
Cranial diabetes insipidus
Nephrogenic diabetes insipidus.
Disorders of K homeostasis
Potassium is the most abundant cation in the organic structure. Entire organic structure K ranges from 37 and 52mmol/kg organic structure weight, and of this 98 % is found in cells, where its concentration is in the scope of 150-160 mmol/kg. The care of intracellular and extracellular gradient is mostly dependent on the omnipresent Na+ , K+ATP ASE enzyme which pumps K anions into the cell for every three Na ions extruded.
Hyperkalaemia ( Harsha Mohan )
Acute nephritic failure
It is defined as a important diminution in nephritic excretory map happening over hours or yearss. This is normally detected clinically by arise in the plasma concentration of the urea or creatinine. Acute nephritic failure may originate as an stray job, but much more commonly occurs in the scene of circulative perturbation associated with terrible unwellness, injury, or surgery ; transeunt nephritic disfunction.
Vascular causes of acute nephritic failure:
Acute cortical mortification
Large vas obstructor
Small vas obstructor
Accelerated stage high blood pressure
Glomerulonephritic and vasculitic causes of ARF
Interstitial Bright’s disease.
Hanta virus disease. ( Europe )
Chronic nephritic failure
It is the clinical syndrome of the metabolic and systemic effects of a gradual, significant and irreversible decrease in the excretory and homeostatic maps of the kidneys. It can be hard to acknowledge because the symptoms and clinical manifestations are non- specific.
Causes of chronic nephritic failure
The most of import causes of chronic kidney disease are diabetes, glomerulonephritis, high blood pressure and other vascular disease.
Arteriopathic nephritic disease and high blood pressure
Infective, clogging and reflux kidney diseases
Familial or familial kidney disease, e.g. polycystic kidneys
Connective tissue diseases
Reflux kidney disease
Renal bone disease is a major cause of disablement in patients with terminal nephritic failure ( Arthur. C. Guyton ) .
MECHANISM OF NEPHROTOXICITY BY PARACETAMOL
Paracetamol induced kidney failure occurred as a consequence of terrible hepatic failure. In the presence of terrible hepatotoxicity that precludes further hepatic metamorphosis of the parent paracetamol, there may be spillover of paracetamol to the kidney where it will be metabolized. Nephrotoxicity so consequences when there is an deficient glutathione in the nephritic parenchyma. This was ab initio interpreted as a hepatorenal syndrome. When paracetamol is metabolized in both liver and kidney, nephrotoxicity may happen independently of hepatotoxicity depending on the balance of metamorphosis and glutathione shops with bin the kidney. Biotransformation in the kidney of paracetamol to a reactive electrophile contributes to covalent binding and subsequent nephrotoxicity. As a cytochrome p-450 is the terminal oxygenase commanding most drug oxidization in the kidney, liver, and other tissues and because of this enzyme system is concentrated primarly in the nephritic cerebral mantle, it is likely that metabolic inactivation of paracetamol to an arylating metabolite might be responsible for the nephritic lesion merely as it is for the hepatic hurt. Compared to the liver, the cytochrome p-450 enzymes in the kidney are less able to detoxicate paracetamol. Thus the nephritic glutathione shops are depleted more quickly and kidney cell hurt occurs as acute cannular mortification.
In human life O is really indispensable, without oxygen we can non last. Our evolutionary ascendants developed defence mechanisms that can minimise the toxic effects of O, without this protection causes the terminal of life. Natural defences are imperfect ; the harm of the cells caused by O can be minimized by utilizing antioxidants. A batch of research plants are made in this past decennaries. In this survey the metabolites produced by the O species and with research plants they have learned how to forestall the diseases caused by the reactive O species. Now research plants are making for bettering the antioxidant activity ( Lillian, 1995 ) .
Free groups of different signifiers are invariably generated for specific metabolic demand and quenched by an efficient antioxidant web in the organic structure. When the coevals of these species exceeds the degrees of antioxidant mechanism, it leads to oxidative harm of tissues and biomolecules, finally taking to disease conditions, particularly degenerative diseases. Many works infusions and phytochemicals have been shown to hold antioxidant/free extremist scavenging belongingss and it has been established as one of the mechanisms of their action ( Dubey et al. , 2009 ) .
Reactive O species ( ROS ) such as O2i‚· , H2O2 and OHi‚· are extremely toxic to cells. Cellular antioxidant enzymes and the free extremist scavengers usually protect a cell from toxic effects of the ROS. When coevals of the ROS overtakes the antioxidant defence of the cells, oxidative harm of the cellular supermolecules ( lipoids, proteins and nucleic acid ) occurs, taking eventually to assorted pathological conditions ( Bandyopadhyay et al. , 1999 ) .
Reactive N species ( RNS ) are the merchandises of normal cellular metamorphosis. NOaˆ? is a little molecule that contains one odd negatron on the antibonding ( 2Iˆ*y ) orbital and is, hence, a extremist. NOaˆ? is generated in biological tissues by specific azotic oxide synthases ( NOSs ) . Overproduction of reactive N species is called nitrosative emphasis. This may happen when the coevals of reactive N species in a system exceeds the system ‘s ability to neutralize and extinguish them. Nitrosative emphasis may take to nitrosylation reactions that can change the construction of proteins and so suppress their normal map ( Valko et al. , 2006 ) .
Free groups are cardinal to any biochemical procedure and stand for an indispensable portion of aerophilic life and our metamorphosis. They are continuously produced by organic structure ‘s normal use of O such as respiration and some cell mediated immune maps. The O ingestion inherent in cell growing leads to the coevals of reactive O species ( ROS ) ( Gulcin et al. , 2007 ) .
Most harmful effects are produced by the reactive O species ( ROS ) in our organic structure, ROS are act as oxidizers. Free group is a chemical species which have a lone brace of negatrons at its outer orbit, so it is unstable and more reactive. Examples are hydroxyl extremist, azotic oxide extremist, superoxide extremist, lipid peroxyl extremist and non groups are hydrogen peroxide, vest O, hypochlorous acid and ozone.
General characteristics of a free extremist reaction
Free extremist reactions take three distinct identifiable stairss
Initiation measure: Formation of groups
Propagation measure: It is the bosom of a free extremist reaction. In this measure, the needed free group is regenerated repeatedly, which would take the reaction to finish.
Termination measure: It involves the devastation of free extremist intermediates ( Manavalan and Ramasamy, 2001 )
I. Initiation measure
II. Propagation measure
Ri‚· + O2 i‚® RO2i‚·
III. Termination measure
Where HI and X are concatenation inhibitors.
Beginnings OF FREE RADICALS
Exogenous free groups
Endogenous free groups
Exogenous beginnings of free groups are automobile exhaust exhausts, UV radiation, electromagnetic radiation, cosmic radiation, interaction with chemicals, coffin nail fume, combustion of organic affair during cookery, forest fires, volcanic activities, radioactive decay-i?? , i?? and i?§ radiation, buoy uping peculiarly oxides of N, by-product of O metamorphosis ( Illness causes the organic structure to bring forth greater sums of harmful groups than in healthy status ) . Industrial wastewaters, extra chemicals, alcoholic consumption, certain drugs, asbestos, certain pesticides and weedkillers, some metal ions and fungous toxins inflict oxidative emphasis ( Irshad and Chaudhuri, 2002 ) .
These are internally generated beginnings of free groups ; they include cyclo oxygenation, lipooxygenation, lipid peroxidation, arachidonate tracts, peroxisomes, xanthine oxidase, redness, chondriosome, cytochrome-P450, scavenger cells, reaction affecting Fe and other passage metals, neutrophils stimulated by exposure to microbes, re-perfusion of ischemic variety meats ( Singh et al. , 2004 ) .
TYPES OF FREE RADICALS
Superoxide extremist ( O2i‚· )
Superoxide anion is a decreased signifier of molecular O created by having one negatron. Superoxide anion is an initial free group formed from mitochondrial negatron conveyance systems. Mitochondria generate energy utilizing four negatron concatenation reactions, cut downing O to H2O. Some of the negatrons get awaying from the concatenation reaction of chondriosomes straight react with O and signifier superoxide anions. The superoxide anion plays an of import function in the formation of other reactive O species such as H peroxide ( H2O2 ) , hydroxyl extremist ( OHi‚· ) or singlet O ( Oi‚· ) in populating systems. The superoxide anion can respond with azotic oxide ( NOi‚· ) and form peroxynitrite ( ONOOi‚· ) , which can bring forth toxic compounds such as hydroxyl extremist and azotic oxide.
Hydrogen peroxide ( H2O2 )
Hydrogen peroxide is the most stable reactive O species. H2O2 is the primary merchandise of the decrease of O by assorted oxidase such as xanthine oxidase, uricase, D-amino acid oxidase and i??-hydroxy acid oxidase localized in peroxisome. Research shows that the H2O2 is the most effectual species for cellular hurt. The good known Fenton reaction is initiated when Fe2+ comes in contact with H2O2. Ions of Cu, Co, and Ni can besides take part in a similar reaction.
Fe2+ + H2O2 Fe3+ + i‚·OH + OH-
H2O2 besides reacts with O2i‚· to originate with Haber-Weiss reaction bring forthing i‚·OH in presence of Fe2+ .
O2i‚· + H2O2 O2 + i‚·OH + OH-
The most of import map of H2O2 is its function as an intracellular signaling molecule ( Ray et al. , 2000 ) .
Hydroxyl groups ( OHi‚· )
Hydroxyl extremist is extremely reactive. It may respond with any molecule nowadays in the cells and hence they are short lived. The life span of OHi‚· at 37i‚°C is 10-9 sec. The hydroxyl group is formed from H peroxide in a reaction catalyzed by metal ions ( Fe+ or Cu+ ) , frequently bound in complex with different proteins or other molecules. This is known as the Fenton reaction.
H2O2 + Cu+/ Fe2+ OHi‚·+OH- + Cu+/Fe3+ aˆ¦aˆ¦aˆ¦aˆ¦.. ( 1 )
A Superoxide besides plays an of import function in connexion with reaction 1, by recycling the metal ions.
Cu2+ / Fe3+ + O2i‚· Cu+ / Fe2+ + O2… … … … … … … … .. ( 2 )
The amount of reaction 1 and 2 is the Haber-Weiss reaction ; passage metals therefore play an of import function in the formation of hydroxyl groups. Lipid is really sensitive to OHi‚· onslaught and novices LPO ( Lipid per oxidization ) . The hydroxyl group is responsible for DNA harm and LPO.
Nitric oxide ( NOi‚· )
Nitric oxide is an inorganic free extremist incorporating uneven figure of negatrons and can organize a covalent nexus with other molecules by sharing a brace of negatrons. It is synthesized by an enzyme azotic oxide synthase located in assorted tissues and plays an active function in free extremist tumour biological science. NO is synthesized enzymatically from L-arginine by NO syntheses
L-arginine + O2 + NADPH i‚® L-citrulline + NO + NADP+
Nitric oxide is another free group that has an of import biological function. NOi‚· produced in the organic structure relaxes musculuss in blood vass, and lowers blood force per unit area. But, extra NOi‚· produced in instances of terrible infection can be harmful. Unlike HOi‚· or O2i‚· , NOi‚· is a much slower responding extremist and it combines with other free extremist and inhibits farther reaction ( Hussain, 2002 ) .
Xanthine oxidase ( XO )
Xanthine oxidase ( XO ) is a beginning of O derived free groups. XO derives from xanthine dehydrogenase ( XD ) , an initial translational merchandise by proteolysis. In morbid status, big sum of XO and XD are released into the circulation to bring forth important sum of ROMs. XO catalase the oxidization of hypoxanthine to uric acid cut downing O2 by one or two negatrons ensuing in the formation of O2i‚· or H2O2. During reoxygenation ( i.e. reperfusion stage ) it reacts with molecular O, thereby let go ofing superoxide anion groups, H peroxide, and farther hydroxyl groups ( Hussain, 2002 ) .
Hypoxanthine + O2 i‚® Xanthine + O2- . + H2O2
Xanthine + O2 i‚® Uric acid + O2- . + H2O2
MECHANISM OF ACTION OF FREE RADICALS OR ROS FORMATION
Oxygen in the ambiance has two odd negatrons and these odd negatrons have parallel spins. Oxygen is normally non reactive to organic molecules that have paired negatrons with opposite spins. This O is considered to be in a land ( three or inactive ) province and is activated to a vest ( active ) province by two different mechanisms.
Absorption of sufficient energy to change by reversal the spin on one of the odd negatrons
Monovalent decrease ( accept a individual negatron )
Superoxide is formed in the first monovalent decrease reaction which undergoes further decrease to organize H2O2. H2O2 farther gets reduced to hydroxyl groups in the presence of ferric salts ( Fe2+ ) . This reaction was first described by Fenton and subsequently developed by Haber and Weiss ( Daniel et al. , 1998 ) .
DISEASES CAUSED BY THE FREE RADICALS
Free groups originate usually during metamorphosis sometimes the organic structure ‘s immune system cells purposefully create free groups to neutralize virus and bacterium. However environmental factors such as pollution, coffin nail fume and weedkiller can besides bring forth free groups. Normally the organic structure can manage free groups but if antioxidants are unavailable or if the free extremist production is extra so harm can happen.
The formation of free groups and the happening of oxidative emphasis is a common constituent of Parkinson ‘s disease. Patients with Parkinson ‘s disease hold reduced glutathione degrees and free extremist harm is found in the signifier of increased lipid peroxidation and oxidization of Deoxyribonucleic acid bases ( Benzie, 2003 ) .
REACTIVE OXYGEN SPECIES AND DISEASE
Cancer and other malignances
Oxidative emphasis induces a cellular oxidation-reduction instability which has been found to be present in assorted malignant neoplastic disease cells compared with normal cells ; the oxidation-reduction instability therefore may be related to oncogenic stimulation. Permanent alteration of familial stuff ensuing from “ oxidative harm ” incidents represents the first measure involved in mutagenesis and carcinogenesis. DNA mutant is a critical measure in carcinogenesis ( Valko et al. , 2006 ) .
The increased Lipidperoxidation by HOaˆ? extremist and hydroperoxides consequences in acute and chronic alcoholic liver diseases. The ROS and lipid peroxidation may play function in pathogenesis of hepatic fibrosis with loss of normal liver map. The plasma degrees of antioxidant vitamins are low in patients with chronic cholestatic liver diseases ( Irshad and Chaudhuri, 2002 )
ROS through oxidative alterations exert a figure of toxic effects in different biological systems. Such ROS induced event in lung disease is arachidonic acid ( AA ) release and metamorphosis of active merchandises. In the lung, the release of arachidonic acid from membrane edge phospholipids is by phospholipase A2. This reaction occurs due to specific stimulations by endocrines such as adrenaline or bradykinin ( Ray and Hussain, 2002 ) .
Rheumatoid arthritis is an autoimmune disease that causes chronic redness of the articulations and tissue around the articulations with infiltration of macrophages and activated T cells. The pathogenesis of this disease is linked preponderantly with the formation of free groups at the site of redness. T cells isolated from the synovial fluid of patients with arthritic arthritis show marks of reduced intracellular GSH degree ( Valko et al. , 2006 ) .
It is a syndrome characterized by a loss of glucose haemostasis. Hyperglycemia can increase oxidative emphasis and alter the redox potency of glutathione. Decreased consumption of glucose into musculus and adipose tissue leads to chronic extracellular hyperglycaemia ensuing in tissue harm and pathophysiological complications. Increased oxidative emphasis is one of the major causes of the hyperglycemia-induced trigger of diabetic complications ( Irshad and Chaudhuri, 2002 ) .
The ROS-induced oxidative emphasis in cardiac and vascular myocytes has been linked with cardiovascular tissue hurt. Regardless of the direct grounds for a nexus between oxidative emphasis and cardiovascular disease, ROS-induced oxidative emphasis plays a function in assorted cardiovascular diseases such as coronary artery disease, ischaemic bosom disease, high blood pressure, myocardiopathies, cardiac hypertrophy and congestive bosom failure.
The encephalon is peculiarly exposed to oxidative harm because of its high O use, its high content of oxidisable polyunsaturated fatty acids and the presence of redox-active metals ( Cu, Fe ) . Oxidative emphasis additions with age and therefore it can be considered as an of import causative factor in several neurodegenerative diseases like Alzheimer ‘s and Parkinson ‘s disease particularly for older persons ( Valko et al. , 2006 ) .
Inflammatory cells ( granulocytes, macrophages, some T-lymphocytes ) produce active species of O as portion of the microbicidal or citocidal systems. The active O species can modulate specific elements of the inflammatory response invitro, include protein immunomodulatory substances such as granulocyte migratory factors PGs, cyclic bases, every bit good as formed elements such as thrombocytes ( Irshad and chaudhuri, 2002 ) .
Aging in worlds is associated with alterations in physical features and the diminution of many physiological maps. Increased accretion of free groups increases the hazard of assortment of oxidative emphasis in older persons. These groups are capable of doing programmed cell death, mortification and cell decease.
Exposure of exogenic beginnings of oxidizers is high ; organic structure ‘s antioxidant defences may be unable to get by, this status called oxidative emphasis. An instability between proxidants and antioxidants. ( Lillian, 1999 )
Figure: 3 The balance of oxidizers and antioxidants
Antioxidants are the substances which scavenges the oxidization procedure. Antioxidants are a type of complex compounds found in our diet that act as a protective shield for our organic structure against certain black diseases such as arterial and cardiac diseases, arthritis, cataracts and besides premature ageing along with several chronic diseases.
The above definition gives a brief thought about the antioxidants and their map. Recent researches on free extremist made revolution a great alteration in wellness and life manners.
Types of antioxidants
Enzymatic and Non-enzymatic.
Antioxidant derived from natural and dietetic beginnings.
Antioxidants based on defence mechanism.
Superoxide dismutase ( SOD ) : – Turf is an endogenously produced intracellular enzyme nowadayss every cell in the organic structure. SOD appears in 3 signifiers harmonizing to the catalytic metal nowadays in the active site.
Glutathione peroxidase ( GSH ) : – It is normally found in chondriosome and cytosol. Its map is remotion of Hydrogen peroxide and organic hydro-peroxide.
Catalase ( CAT ) : – It is found in chondriosome and cytosol. Its chief map is the remotion of H peroxide ( H2O2 ) .
Carotenoids: – It is a lipid soluble antioxidants, normally seen in membrane tissue. The chief map is the remotion of reactive O species.
Bilirubin: – It is produced by haem metamorphosis found in blood. The chief map is to move as extracellular antioxidants.
Glutathione: – It is a non protein thiol and found in cells. It has the belongings of cellular oxidant defence.
Alpha-lipoic acid: – It is endogenous thiol. Its belongings is by functioning replacement for glutathione, recycling vitamin C.
Vitamin C: – It is found in aqueous stage of cell. Its belongings is act as free extremist scavenger and besides acts in the recycle of vitamin E.
Vitamin Tocopherol: – It is found in cells. Function is concatenation interrupting antioxidant.
Uric acid: – It is a merchandise of purine metamorphosis. Its belongings is scavenging of hydroxyl ( OH ) group.
Antioxidant derived from natural and dietetic beginnings
Plants are good beginning of antioxidants. The foliages of the most medicative workss have the antioxidant belongings. The chemical components contained in the foliages are causative for the antioxidant belongings ( Eg: – Flavanoids, carotnoids, alkaloids, phenolic intoxicants etc. ) . Daily diet contains full of antioxidants like veggies, fruits, tea, wine etc. Secondary merchandises of workss which are working as antioxidant are,
Chlorophyll derived functions.
Phenolic resins – coumarines, flavanoids.
Poly phenoplasts – tannic acids, proanthocynidine.
Nitrogen incorporating compounds – alkaloids, indoles.
Antioxidant based on defence mechanism
Preventive antioxidants: – It will stamp down the free extremist formation, enzymes such as peroxidase, catalase, lactoferrin, carotenoids etc.
Extremist scavenging antioxidants: – It will stamp down the concatenation induction reaction, like Vitamin C and carotenoids.
Repair and de novo antioxidant: – It consist of proteolytic enzymes, it besides repairs the Deoxyribonucleic acid of enzymes and familial stuffs.
Enzyme inhibitor antioxidants: – It induces production and reaction of free groups and conveyance of appropriate antioxidants to allow active site.
MECHANISM OF ACTION OF ANTIOXIDANTS
Physical barriers forestalling ROS coevals or ROS entree to of import biological sites.
E.g. UV filters, cell membranes
Chemical traps / sinks ‘absorb ‘ energy and negatrons slaking ROS.
E.g. Carotenoids, anthocyanidins
Catalytic systems neutralize or divert ROS.
E.g. SOD, catalase and glutathione peroxidase
Adhering / inactivation of metal ion prevents coevals of ROS by Haber-Weiss reaction.
E.g. Ferritin, catechins
Sacrificial and concatenation breakage antioxidants scavenge and destroy ROS.
E.g. Ascorbic acid ( Vit.C ) , Tocopherol ( Vit E ) , uric acid, glutathione, flavonoids ( Benzie, 2003 ) .
Interaction between antioxidants
Man-made ways antioxidants are interacting one antioxidant protect another against oxidative devastation. Vitamin E can protect beta provitamin A molecule from oxidization and saving consequence is taking topographic point.