Sharma Nidhi et al. IRJP 2012, 3 (7) INTERNATIONAL RESEARCH JOURNAL OF PHARMACY www.irjponline.com ISSN 2230 – 8407 Review Article

DIFFERENT MODELS OF AND RELATED DISEASES: A REVIEW Singh Robin*, Kumar Sunil, Rana A.C., Sharma Nidhi Rayat Institute of Pharmacy, Railmajra, Dist. Nawanshahar, Near Ropar, Punjab, India

Article Received on: 19/04/12 Revised on: 16/05/12 Approved for publication: 21/06/12

*Email: [email protected]

ABSTRACT The liver is among the most complex and important organs in the human body. Its primary function is to control the flow and safety of substances absorbed from the digestive system before distribution of these substances to the systemic circulatory system. Hepatotoxicity implies chemical-driven liver damage. Chemicals that cause liver injury are called hepatotoxins. Hepatic injury leads to disturbances in transport function of hepatocytes resulting in leakage of plasma membrane thereby causing an increased level in serum. There are many diseases that are related with hepatotoxicity caused by certain chemicals or hepatotoxins. Herbal medicines are great demand in various chemicals and drugs disordered hepatic, the developed world for primary health care because of their efficacy, safety, lesser side effects and narrow therapeutic window. This review focus on liver, its function, liver diseases and different models of hepatotoxicity. Keywords: Hepatotoxicity, CCl4, mercury, , Hepatitis, Jaundice etc.

INTRODUCTION:- endothelial organ in the body as such has important immune Hepatotoxicity implies chemical-driven liver damage. Certain function in maintaining body veracity. Damaging hepatocyte medicinal agents, when taken in overdoses and sometimes results in the activation of innate immune system like kupffer even when introduced within therapeutic ranges, may injure cells (KC), natural killer (NK) cells, and natural killer T the organ. Other chemical agents, such as those used in (NKT) cells and result in producing proinflammatory laboratories (e.g. ccl4, paracetamol) and industries (e.g. lead, mediators such as tumor necrosis factor-α (TNF), interferon-ᵞ ), natural chemicals (e.g. microcystins, aflatoxins) and (IFN), and interleukin-β (IL) produced liver injury. Many herbal remedies (Cascara sagrada, ephedra) can also induce agents damage mitochondria, an intracellular organelle that hepatotoxicity. Chemicals that cause liver injury are called produces energy. In mitochondria hepatocellular death is a hepatotoxins. These agents are convert in chemically reactive direct result of drugs acting on these organelles (e.g., drug metabolites in liver, which have the ability to interconnect accumulation, inhibition of electron transport and fatty acid with cellular macromolecules such as protein, lipids and oxidation, or depletion of anti-oxidant defenses). An indirect nucleic acids, leading to protein dysfunction, lipid per result ensuing from mitochondrial participation in programs oxidation, DNA damage and oxidative stress. This damage of of cell death. These programs lead to necrosis or apoptosis; cellular function can dismiss in cell death and likely liver they are mediated through signaling mechanisms arising at failure. More than 900 drugs have been implicated in causing the cell membrane (e.g., death receptors) or in subcellular liver injury and it is the most common reason for a drug to be compartments (e.g., the endoplasmic reticulum or cell withdrawn from the market. Chemicals often cause nucleus). Its dysfunction releases excessive amount of subclinical injury to liver which manifests only as abnormal oxidants which, in turn, injure hepatic cells. Non- liver enzyme tests. Drug-induced liver injury is responsible parenchymal cells such as Kupffer cells, fat storing stellate for 5% of all hospital admissions and 50% of all acute liver cells, and leukocytes (i.e. neutrophil and monocyte) also have failures. More than 75 percent of cases of idiosyncratic drug role in the mechanism hepatotoxicity3. Medicinal plants play reactions result in liver transplantation or death1. Liver plays a key role in the human health care system. Pharmacological a pivotal role in regulating various physiological processes. It medicinal plants play a key role in the evaluation of these is also involved in several vital function, such as , plants and their taxonomical health care system. Herbal secretion and storage. It has great capacity to detoxicate toxic medicines are great demand in various chemicals and drugs substances and synthesize useful principle. It helps in the disordered hepatic, the developed world for primary health maintenance, performance and regulating homeostasis of the care because of their efficacy, safety, lesser side effects and body. It involved with almost all the biochemical pathways to narrow therapeutic window. Therefore, the use of herbal growth, fight against disease, nutrient supply, energy drugs is much safer than synthetic product available in the provision and reproduction. It aids metabolism of market. Herbal remedies support natural healing phenomena carbohydrate, protein and fat, detoxification, secretion of bile through blocking the progression of the degenerative and storage of vitamines2. The role played by this organ in pathological processes. Modern medicine offers limited the removal of substances from the portal circulation makes it success in providing effective cure and there is a severe need susceptible to first and persistent attack by offending foreign to develop new drug capable of healing toxic liver damages. compounds, culminating in liver dysfunction. These In traditional system of medicine, plant were claimed to be hepatotoxic agents activated some activity in the effective and used successfully to alleviate multiple liver cytochrome p-450 system such as CYP2E1 also leads to disorders. Ayurveda has a clinical speciality called rasayana, oxidative stress. Injury to hepatocyte and bile duct cells lead which prevent disease and counteracts the aging process by to accumulation of bile acid inside liver. This promotes means of optimization of homeostasis. It has been reported further liver damage. Liver is also the major reticulo- that rasayanas are rejuvenators, nutritional supplements and

Page 86 Sharma Nidhi et al. IRJP 2012, 3 (7) possess strong antioxidant activity. Hepatic injury leads to less toxic urea for excretion in urine. Hepatic cells synthesize disturbances in transport function of hepatocytes resulting in plasma protein such as alpha and beta globulin, albumin, pro- leakage of plasma membrane thereby causing an increased thrombin and fibrinogen. enzyme level in serum. All the hepatotoxic used in the Haematological function: present study induced ROS production in the body. This The liver produces coagulation factors I (fibrinogen), II leads to depletion of antioxidant status of hepatic tissue and (prothrombin), V, VII, IX, X and XI, as well as protein induced lipid peroxidation degradation of bio membrane in C, protein S and antithrombin. In the first trimester foetus, the control group. Administration of antioxidant, which can the liver is the main site of red blood cell production. By the scavenge the free radicals, could reduced the hepatic injury. 32nd week of gestation, the bone marrow has almost There are many herbal medicine plant having antioxidant completely taken over that task. properties which show hepatoprotective activity4. Secretion and excretion of bile: LIVER AND ITS FUNCTION: Bile is partially an excretory product and partially a digestive LIVER: secretion. Each day the hepatic cells secrete 800-1000ml of The liver is among the most complex and important organs in bile, a yellow or olive green liquid. It has PH of 7.6- 8.6 . the human body. Its primary function is to control the flow Bile mainly consists of , bile salts, cholesterol, a and safety of substances absorbed from the digestive system phospholipid called lecithin, bile pigments and several ions. before distribution of these substances to the systemic The principle bile pigment is bilirubin. When worn out red circulatory system . It lies below the diaphragm in the blood cells broken down, iron, globin’s and bilirubin (derived abdominal pelvic region of the abdomen. The liver is a from heam) are released. reddish brown organ with four lobes of unequal size and Breakdown: shape. It is both the largest internal organ and the largest The breakdown of insulin and other hormones. The liver gland in the human body. It is connected to two large blood glucoronidates bilirubin, facilitating its excretion into bile. vessels, one called the hepatic artery and one called the portal The liver breaks down or modifies toxic substances (e.g., vein. It constitutes about 2.5% of an adult’s body weight. methylation) and most medicinal products in a process During rest, it receives 25% of the cardiac output via the called . This sometimes results in toxication, hepatic portal vein and hepatic artery. The hepatic portal vein when the metabolite is more toxic than its precursor. carries the absorbed nutrients from the GI tract to the liver, Preferably, the toxins are conjugated to avail excretion in bile which takes up, stores, and distributes nutrients and vitamins. or urine. The liver converts ammonia to urea (urea cycle). It produced bile, an alkaline compound which aids in Other functions: digestion via the emulsification of lipids. Two major types of The liver stores a multitude of substances, including glucose cells populate the liver lobes: parenchymal and non- (in the form of glycogen), vitamin A (1–2 years' parenchymal cells. 80% of the liver volume is occupied by supply), vitamin D (1–4 months' supply), vitamin B12 (1–3 parenchymal cells commonly referred to as hepatocytes. years' supply), iron, and copper. The liver is responsible for Non-parenchymal cells constitute 40% of the total number of immunological effects—the reticulo endothelial system of the liver cells but only 6.5% of its volume. Sinusoidal endothelial liver contains many immunologically active cells, acting as a cells, kupffer cells and hepatic stellate cells are some of the 'sieve' for antigens carried to it via the portal system. The non-parenchymal cells that line the hepatic sinusoid5. liver produces albumin, the major osmolar component FUNCTION OF LIVER6 of blood serum. The liver synthesizes angiotensinogen, a The liver has well over 500 functions and is known as the hormone that is responsible for raising the blood laboratory of the human body. The liver is tied to all bodily pressure when activated by renin, an enzyme that is released processes because it is responsible for filtration of all when the kidney senses low blood pressure. The liver also incoming foods and fluids. The body relies upon the liver to produces insulin-like growth factor 1 (IGF-1), remove toxins so that nutrients supplied to the body are pure a polypeptide protein hormone that plays an important role in and capable of providing nourishment. Many scientists childhood growth and continues to have anabolic effects in believe the liver is connected to, or at least aware, of every adults. The liver is a major site of thrombopoietin production. disease or dysfunction that is happening inside the body. Thrombopoietin is a glycoprotein hormone that regulates the Metabolic function: production of platelets by the bone marrow. Carbohydrate metabolism: LIVER DISEASE: Liver maintains the normal blood glucose level. It can Fatty Liver : converts glucose to glycogen (glycogenesis) when blood Fatty liver, also known as fatty liver disease (FLD), is a sugar level is high and breakdown of glycogen to glucose reversible condition where large vacuoles of triglyceride fat (glycogenolysis) when blood sugar level is low. Also liver accumulate in liver cells via the process of steatosis (i.e. can converts amino acid and lactic acid to glucose abnormal retention of lipids within a cell). Despite having (gluconeogenesis) when blood sugar level is low. multiple causes, fatty liver can be considered a Lipid metabolism: single disease that occurs worldwide in those with Liver stores some triglycerides (neutral fat) breakdown fatty excessive alcohol intake and those who are obese (with or acids into acetyl coenzyme-A, this process is called as without effects of insulin resistance). The condition is also oxidation and converts excess acetyl coenzyme A into ketone associated with other diseases that influence bodies (ketogenesis). It synthesizes lipoproteins. Hepatic fat metabolism. Morphologically it is difficult to distinguish cells synthesize cholesterol and use cholesterol to make bile alcoholic FLD from non alcoholic FLD and both show salts. micro-vesicular and macrovesicular fatty changes at different Protein metabolism: stages. Non-alcoholic fatty liver disease occurs when your The liver delaminates (remove the amino group, NH2) from liver has trouble breaking down fats, causing fat to build up amino acids so that they can be used for ATP production. It in your liver tissue7. converts the resulting toxic ammonia (NH3) into the much Page 87 Sharma Nidhi et al. IRJP 2012, 3 (7) Pathophysiology of fatty liver disease: Types of jaundice: Defects in fat metabolism are responsible for pathogenesis of Jaundice is classified into three categories. FLD which may be due to imbalance in energy consumption 1) Pre-hepatic (haemolytic jaundice): and its combustion resulting in lipid storage or can be a Pre-hepatic jaundice is caused by anything which causes an consequence of peripheral resistance to insulin, whereby the increased rate of hemolysis (breakdown of red blood cells). transport of fatty acids from adipose tissue to the liver is In tropical countries, malaria can cause jaundice in this increased. Impairment or inhibition of receptor molecules manner. Certain genetic diseases, such as sickle cell anemia, (PPAR-α, PPAR-γ and SREBP1) that control the enzymes spherocytosis, thalassemia and glucose 6-phosphate responsible for the oxidation and synthesis of fatty acids dehydrogenase deficiency can lead to increased red cell lysis appears to contribute towards fat accumulation. In addition, and therefore hemolytic jaundice. Commonly, diseases of the alcoholism is known to damage mitochondria and other kidney, such as hemolytic uremic syndrome, can also lead to cellular structure further impairing cellular energy coloration. Defects in bilirubin metabolism also present as mechanism. On the other hand non alcoholic FLD may begin jaundice, as in Gilbert's syndrome (a genetic disorder of as excess of un metabolised energy in liver cells. Hepatic bilirubin metabolism which can result in mild jaundice, steatosis is considered reversible and to some extent non which is found in about 5% of the population) and Crigler- progressive if there is cessation or removal of underlying Najjar syndrome. In jaundice secondary to hemolysis, the cause. Fatty change represents the intra-cytoplasmic increased production of bilirubin, leads to the increased accumulation of triglyceride (neutral fats). At the beginning, production of urine-uro bilinogen. Bilirubin is not usually the hepatocytes present small fat vacuoles (liposomes) around found in the urine because unconjugated bilirubin is not the nucleus (microvesicular fatty change). In this stage liver water-soluble, so, the combination of increased urine-uro cells are filled with multiple fat droplets that do not displace bilinogen with no bilirubin (since, unconjugated) in urine is the centrally located nucleus. In the late stages, the size of the suggestive of hemolytic jaundice. vacuoles increase pushing the nucleus to the periphery of the 2) Hepatocellular (hepatic jaundice): cell giving characteristic signet ring appearance Hepatocellular (hepatic) jaundice can be caused by acute or (macrovesicular fatty change). These vesicles are well chronic hepatitis, hepatotoxicity, cirrhosis, drug induced delineated and optically "empty" because fats dissolve during hepatitis and alcoholic liver disease. Cell necrosis reduces the tissue processing. Large vacuoles may coalesce and produce liver's ability to metabolize and excrete bilirubin leading to a fatty cysts which are irreversible lesions. Macrovesicular buildup of unconjugated bilirubin in the blood. Other causes steatosis is the most common form and is typically associated include primary biliary cirrhosis leading to an increase in with alcohol, diabetes, obesity and corticosteroids. Acute plasma conjugated bilirubin because there is impairment of fatty liver of pregnancy and Reye's syndrome are examples of excretion of conjugated bilirubin into the bile. The blood severe liver disease caused by microvesicular fatty change8. contains abnormally raised amount of conjugated bilirubin JAUNDICE: and bile salts which are excreted in the urine. Jaundice seen Jaundice (also known as icterus; attributive in the newborn, known as neonatal jaundice, is common in adjective: icteric) is a yellowish pigmentation of the skin, newborns as hepatic machinery for the conjugation and the conjunctival membranes over the sclerae (whites of the excretion of bilirubin does not fully mature until eyes), and other mucous membranes caused by approximately two weeks of age. Rat fever (leptospirosis) can hyperbilirubinemia (increased levels of bilirubin in the also cause hepatic jaundice. In hepatic jaundice, there is blood). This hyperbilirubinemia subsequently causes invariably cholestasis10. increased levels of bilirubin in the extracellular fluid. 3) Post-hepatic: Concentration of bilirubin in blood plasma does not normally Post-hepatic jaundice, also called obstructive jaundice, is exceed 1 mg/dL(>17µmol/L). A concentration higher than caused by an interruption to the drainage of bile in the biliary 1.8 mg/dL (>30µmol/L) leads to jaundice. The term jaundice system. The most common causes are gallstones in comes from the French word jaune, meaning yellow. the common bile duct, and pancreatic cancer in the head of Jaundice is often seen in liver disease such as hepatitis or the pancreas. Also, a group of parasites known as "liver liver cancer. It may also indicate leptospirosis or obstruction flukes" can live in the common bile duct, causing obstructive of the biliary tract, for example by gallstones or pancreatic jaundice. Other causes include strictures of the common bile cancer, or less commonly be congenital in origin. Yellow duct, biliary atresia, cholangiocarcinoma, pancreatitis and discoloration of the skin, especially on the palms and the pancreatic pseudocysts. A rare cause of obstructive jaundice soles, but not of the sclera and mucous membranes (i.e. oral is Mirizzi's syndrome. In complete obstruction of the bile cavity) is due to carotenemia a harmless condition important duct, no urobilinogen is found in the urine, since bilirubin has to differentiate from jaundice. The conjunctiva of the eye are no access to the intestine and it is in the intestine that one of the first tissues to change color as bilirubin levels rise bilirubin gets converted to urobilinogen to be later released in jaundice. This is sometimes referred to as scleral icterus. into the general circulation. In this case, presence of bilirubin However, the sclera themselves are not "icteric" (stained (conjugated) in the urine without urine-urobilinogen suggests with bile pigment) but rather the conjunctival membranes that obstructive jaundice, either intra-hepatic or post-hepatic. The overlie them. The yellowing of the "white of the eye" is thus presence of pale stools and dark urine suggests an obstructive more properly termed conjunctival icterus. The term "icterus" or post-hepatic cause as normal feces get their color from bile itself is sometimes incorrectly used to refer to jaundice that is pigments. However, although pale stools and dark urine are a noted in the sclera of the eyes, however its more common and feature of biliary obstruction, they can occur in many intra- more correct meaning is entirely synonymous with jaundice9. hepatic illnesses and are therefore not a reliable clinical feature to distinguish obstruction from hepatic causes of jaundice11.

Page 88 Sharma Nidhi et al. IRJP 2012, 3 (7) Pathophysiology of Jaundice: and treatment usually focuses on preventing progression and The pathological processes that cause jaundice to take their complications. In advanced stages of cirrhosis the only option effect must be understood. Jaundice itself is not a disease, but is a liver transplant. rather a sign of one of many possible underlying pathological Pathophysiology of cirrhosis: processes that occur at some point along the normal The liver plays a vital role in synthesis of proteins (e.g., physiological pathway of the metabolism of bilirubin. When albumin, clotting factors and complement), detoxification and red blood cells have completed their life span of storage (e.g., vitamin A). In addition, it participates in the approximately 120 days, or when they are damaged, their metabolism of lipids and carbohydrates. Cirrhosis is often membranes become fragile and prone to rupture. As each red preceded by hepatitis and fatty liver (steatosis), independent blood cell traverses through the reticulo -endothelial system, of the cause. If the cause is removed at this stage, the changes its cell membrane ruptures when its membrane is fragile are still fully reversible. The pathological hallmark of enough to allow this. Cellular contents, including cirrhosis is the development of scar tissue that replaces hemoglobin, are subsequently released into the blood. The normal parenchyma, blocking the portal flow of blood hemoglobin is phagocytosed by macrophages, and split into through the organ and disturbing normal function. Recent its heme and globin portions. The globin portion, a protein, is research shows the pivotal role of the stellate cell, a cell type degraded into amino acids and plays no role in jaundice. Two that normally stores vitamin A, in the development of reactions then take place with the heme molecule. The cirrhosis. Damage to the hepatic parenchyma leads to first oxidation reaction is catalyzed by the microsomal activation of the stellate cell, which becomes contractile enzyme heme oxygenase and results in biliverdin (green (called myofibroblast) and obstructs blood flow in the color pigment), iron and carbon monoxide. The next step is circulation. In addition, it secretes TGF-β1, which leads to a the reduction of biliverdin to a yellow color tetrapyrol fibrotic response and proliferation of connective tissue. pigment called bilirubin by cytosolic enzyme biliverdin Furthermore, it secretes TIMP 1 and 2, naturally occurring reductase. This bilirubin is "unconjugated," "free" or inhibitors of matrix metallo proteinases, which prevents them "indirect" bilirubin. Approximately 4 mg of bilirubin per kg from breaking down fibrotic material in the of blood is produced each day. The majority of this bilirubin extracellular matrix. The fibrous tissue bands (septa) separate comes from the breakdown of heme from expired red blood hepatocyte nodules, which eventually replace the entire liver cells in the process just described. However approximately 20 architecture, leading to decreased blood flow throughout. percent comes from other heme sources, including The spleen becomes congested, which leads to hypersplenism ineffective erythropoiesis, and the breakdown of other heme- and increased sequestration of platelets. Portal hypertension containing proteins, such as muscle myoglobin and is responsible for most severe complications of cirrhosis13. cytochromes12. HEPATITIS: Hepatic events: Hepatitis (plural hepatitides) is a medical condition defined The unconjugated bilirubin then travels to the liver through by the inflammation of the liver and characterized by the the bloodstream. Because this bilirubin is not soluble, presence of inflammatory cells in the tissue of the organ. The however, it is transported through the blood bound to serum condition can be self-limiting (healing on its own) or can albumin. Once it arrives at the liver, it is conjugated progress to fibrosis (scarring) and cirrhosis. Hepatitis may with (to form bilirubin diglucuronide, or just occur with limited or no symptoms, but often leads "conjugated bilirubin") to become more water soluble. The to jaundice, anorexia (poor appetite) and malaise. Hepatitis is reaction is catalyzed by the enzyme UDP-glucuronyl acute when it lasts less than six months and chronic when it transferase. This conjugated bilirubin is excreted from the persists longer. A group of viruses known as the hepatitis liver into the biliary and cystic ducts as part of bile. Intestinal viruses cause most cases of hepatitis worldwide, but it can bacteria convert the bilirubin into urobilinogen. From here also be due to toxins (notably alcohol, certain medications, the urobilinogen can take two pathways. It can either be some industrial organic solvents and plants), further converted into stercobilinogen, which is other infections and autoimmune diseases14. then oxidized to stercobilin and passed out in the feces, or it Acute: can be reabsorbed by the intestinal cells, transported in the Initial features are of nonspecific flu-like symptoms, common blood to the kidneys, and passed out in the urine as the to almost all acute viral infections and may include malaise, oxidised product urobilin. Stercobilin and urobilin are the muscle and joint aches, fever, nausea or vomiting, products responsible for the coloration of feces and urine, diarrhoea, and headache. More specific symptoms, which can respectively be present in acute hepatitis from any cause, are: profound CIRRHOSIS: loss of appetite, aversion to smoking among smokers, dark Cirrhosis is a consequence of chronic liver disease urine, yellowing of the eyes and skin (i.e., jaundice) characterized by replacement of liver tissue by fibrosis, scar and abdominal discomfort. Physical findings are usually tissue and regenerative nodules (lumps that occur as a result minimal, apart from jaundice in a third and of a process in which damaged tissue is regenerated) leading tender hepatomegaly (swelling of the liver) in about 10%. to loss of liver function. Cirrhosis is most commonly caused Some exhibit lymphadenopathy (enlarged lymph nodes, in by alcoholism, hepatitis B and C, and fatty liver disease, but 5%) or splenomegaly (enlargement of the spleen, in 5%). has many other possible causes. Some cases areidiopathic, Acute viral hepatitis is more likely to be asymptomatic in i.e. of unknown cause . Ascites (fluid retention in the younger people. Symptomatic individuals may present after abdominal cavity) is the most common complication of convalescent stage of 7 to 10 days, with the total illness cirrhosis, and is associated with a poor quality of life, lasting 2 to 6 weeks. A small proportion of people with acute increased risk of infection, and a poor long-term outcome. hepatitis progress to acute liver failure, in which the liver is Other potentially life-threatening complications are hepatic unable to clear harmful substances from the circulation encephalopathy (confusion and coma) and bleeding (leading to confusion and coma due to hepatic from esophageal varices. Cirrhosis is generally irreversible, encephalopathy) and produce blood proteins (leading Page 89 Sharma Nidhi et al. IRJP 2012, 3 (7) to peripheral edema and bleeding). This may become life- cent of hepatitis C patients get cirrhosis where all those threatening and occasionally requires a liver transplant15. people who acquire cirrhosis are at risk of developing liver Chronic: cancer. Donated blood must be tested for HCV. Chronic hepatitis often leads to nonspecific symptoms such Hepatitis D: HDV (Hepatitis D Virus) affects only that as malaise, tiredness and weakness, and often leads to no person who is already suffering from HBV. Unprotect sexual symptoms at all. It is commonly identified on blood intercourse, infected blood, and perforation of the skin are tests performed either for screening or to evaluate nonspecific once again the causes. Swelling strikes to the liver of symptoms. The occurrence of jaundice indicates advanced hepatitis D patient. liver damage. On physical examination there may be Hepatitis E: Water that contains HEV (Hepatitis E Virus) enlargement of the liver. Extensive damage and scarring of can infect the drinker. Swelling in the liver occur but without liver (i.e. cirrhosis) leads to weight loss, easy bruising and any serious consequences. Anal or oral sex is also considered bleeding tendencies, peripheral edema (swelling of the legs) to be a reason for the infection. and accumulation of ascites (fluid in the abdominal cavity). Hepatitis X: Any infection that is not coming under teh Eventually, cirrhosis may lead to various complications: category of any of teh above viruses are name hepatitis X. esophageal varices (enlarged veins in the wall of the Simply narrating it is teh inflammation caused by an esophagus that can cause life-threatening bleeding) hepatic undiscovered or unknown virus. encephalopathy (confusion and coma) and hepatorenal Hepatitis G: Hepatitis caused by HGV (Hepatitis G Virus) is syndrome (kidney dysfunction).Acne, abnormal hepatitis G. Casually there are no signs or symptoms. In case menstruation, lung scarring, inflammation of the thyroid there are symptoms then they are very mild. gland and kidneys may be present in women Pathophysiology of Hepatitis: with autoimmune hepatitis16. The liver, like all organs, responds to injury in a limited Non-infection hepatitis- number of ways and a number of patterns have been All types of inflammation are not bad. The hepatitis caused identified. Liver biopsies are rarely performed for acute by alcohol or other toxic material, medication or chemicals is hepatitis and because of this the histology of chronic hepatitis bad for liver and inflames it. Any immune related injury, a is better known than that of acute hepatitis. metabolic disorder and a genetic problem can result in Acute: hepatitis. Liver damage caused as a result of obesity can In acute hepatitis the lesions (areas of abnormal tissue) result in hepatitis. All these types of hepatitis are called non- predominantly contain diffuse sinusoidal and portal infectious as they are bound to stay in the body of only one mononuclear infiltrates (lymphocytes, plasma cells, Kupffer person and not transfer from one person to another. cells) and swollen hepatocytes. Acidophilic cells Infectious hepatitis: (Councilman bodies) are common. Hepatocyte regeneration There are five mainstream types of infectious hepatitis (the and cholestasis (canalicular bile plugs) typically are present. hepatitis that can infect from one person to another) that are Bridging hepatic necrosis (areas of necrosis connecting two respectively caused by hepatitis virus A , hepatitis B, or more portal tracts) may also occur. There may be some hepatitis virus C, hepatitis virus D, and hepatitis virus E lobular disarray. Although aggregates of lymphocytes in where hepatitis virus X and hepatitis virus G also lead to portal zones may occur these are usually neither common nor hepatitis. prominent. The normal architecture is preserved. There is no Hepatitis A: It is caused by water or food infected with the evidence of fibrosis or cirrhosis (fibrosis plus regenerative virus HAV (hepatitis A Virus). Whether oral or anal contact nodules). In severe cases prominent hepatocellular necrosis during sexual intercourse can also lead to the infection. The around the central vein (zone 3) may be seen. virus does not lead to chronic disease and almost everyone In submassive necrosis a rare presentation of acute hepatitis – infected with HAV recovers. there is widespread hepatocellular necrosis beginning in Hepatitis B: It is a sexually transmitted disease and is caused the centrizonal distribution and progressing towards portal by HBV (Hepatitis B Virus). The virus is acquired by contact tracts. The degree of parenchymal inflammation is variable with any body fluid such as infected blood or semen. and is proportional to duration of disease. Two distinct Liver of the infected person swells with HBV. Severe patterns of necrosis have been recognised: zonal coagulative damage to the liver caused by the virus can result in liver necrosis or panlobular (nonzonal) necrosis. Numerous cancer. Some patients of hepatitis B gets chronic, remains macrophages and lymphocytes are present. Necrosis and infected throughout their lives or for very long time. Donated inflammation of the biliary tree occurs. Hyperplasia of the blood must be tested for hepatitis before injecting into a surviving biliary tract cells may be present. Stromal patient. Hepatitis B is acquired by: Unprotected sex, without haemorrhage is common17. using condom, with the affect or by the use of a syringe that Chronic: was already used by the infected patient (it usually happens Chronic active hepatitis was the term used to described cases in the case of drug addicts who exchange syringes and people of hepatitis for more than 6 months with portal based who inject steroids).In case someone pricked in an accident inflammation, fibrosis, disruption of the terminal plate and or pierce his or her skin while making tattoos the virus enters piecemeal necrosis. This term has now been replaced by the the body if the needle or the surface is not sterilized. All diagnosis of 'chronic hepatitis with piecemeal (periportal) those people who serve in health care projects are at risk of necrosis (or interface hepatitis) with or without fibrosis. getting infected as a result of any accident. The exchange of Chronic persistent hepatitis was the term used to describe toothbrush or razor can also spread the HBV. Milk of the chronic hepatitis with no significant periportal necrosis or infected mother can affect the baby. Bite of Hepatitis B regeneration with a fairly dense mononuclear portal infiltrate. patient can result in transferring HBV. Councilman bodies are frequently seen within the lobule. Hepatitis C: It is caused by the direct contact with the blood This condition is now referred to as 'chronic hepatitis without of infected person. It is caused by HCV (Hepatitis C Virus) piecemeal necrosis (or interface hepatitis). Chronic lobular that swells the liver and damages it afterwards. About 20 per hepatitis was the term used to describe chronic hepatitis with Page 90 Sharma Nidhi et al. IRJP 2012, 3 (7) persistent parenchymal focal hepatocyte necrosis (apoptosis) unintentional weight loss,abdominal pain, especially in the with mononuclear sinusoidal infiltrates. This is now referred upper -right part, nausea, emesis, or fatigue19. to as 'chronic hepatitis without piecemeal necrosis (or Pathophysiology of Hepatocellular carcinoma: interface hepatitis). These terms have since Hepatocellular carcinoma, like any other cancer, develops been deprecated. This was done because it was realised that when there is a mutation to the cellular machinery that causes these conditions could alter over time and what might have the cell to replicate at a higher rate and/or results in the cell been regarded as a relatively benign lesion could still avoiding apoptosis. In particular, chronic infections progress to cirrhosis. The simpler term 'chronic hepatitis' is of hepatitis B and/or C can aid the development of now preferred in association with the causative agent (when hepatocellular carcinoma by repeatedly causing the body's known) and a grade based on the degree of inflammation, own immune system to attack the liver cells, some of which piecemeal or bridging necrosis (interface hepatitis) and the are infected by the virus, others merely bystanders. While this stage of fibrosis. Several grading systems have been proposed constant cycle of damage followed by repair can lead to but none have been adopted universally. Cirrhosis is a diffuse mistakes during repair which in turn lead to carcinogenesis, process characterized by regenerative nodules that are this hypothesis is more applicable, at present, to hepatitis C. separated from one another by bands of fibrosis. It is the end Chronic hepatitis C causes HCC through the stage stage for many chronic liver diseases. The pathophysiological of cirrhosis. In chronic hepatitis B, however, the integration process that results in cirrhosis is as follows: hepatocytes are of the viral genome into infected cells can directly induce a lost through a gradual process of hepatocellular injury and non-cirrhotic liver to develop HCC. Alternatively, repeated inflammation. This injury stimulates a regenerative response consumption of large amounts of ethanol can have a similar in the remaining hepatocytes. The fibrotic scars limit the effect. Besides, cirrhosisis commonly caused by alcoholism, extent to which the normal architecture can be reestablished chronic hepatitis B and chronic hepatitis C. The toxin as the scars isolate groups of hepatocytes. This results in aflatoxin from certain Aspergillus species of fungus is a nodules formation. Angiogenisis (new vessel formation) and aids carcinogenesis of hepatocellular cancer accompanies scar production which results in the formation by building up in the liver. The combined high prevalence of of abnormal channels between the central hepatic veins and rates of aflatoxin and hepatitis B in settings the portal vessels. This in turn causes shunting of blood like China and West Africa has led to relatively high rates of around the regenerating parenchyma. Normal vascular heptatocellular carcinoma in these regions. Other viral structures including the sinusoidal channels may be hepatitides such as hepatitis A have no potential to become a obliterated by fibrotic tissue leading to portal hypertension. chronic infection and thus are not related to hepatocellular The overall reduction in hepatocyte mass, in conjunction with carcinoma. the portal blood shunting, prevents the liver from HEPATIC ENCEPHALOPATHY: accomplishing its usual functions – the filtering of blood Hepatic encephalopathy (also known as portosystemic from the gastrointestinal tract and serum protein production. encephalopathy) is the occurrence of confusion, altered level These changes give rise to the clinical manifestations of of consciousness and comaas a result of liver failure. In the cirrhosis18. advanced stages it is called hepatic coma or coma HEPATOCELLULAR CARCINOMA: hepaticum. It may ultimately lead to death . It is caused by Hepatocellular carcinoma (HCC, also called malignant accumulation in the bloodstream of toxic substances that are hepatoma) is the most common type of liver cancer. Most normally removed by the liver. The diagnosis of hepatic cases of HCC are secondary to either a viral hepatitis encephalopathy requires the presence of impaired liver infection (hepatitis B or C) or cirrhosis (alcoholism being the function and the exclusion of an alternative explanation for most common cause of hepatic cirrhosis). Liver cancer the symptoms. Blood tests (ammonia levels) may assist in the (hepatocellular carcinoma) is a cancer arising from the liver. diagnosis. Attacks are often precipitated by an intercurrent It is also known as primary liver cancer or hepatoma. The problem, such as infection or constipation. Hepatic liver is made up of different cell types (for example, bile encephalopathy is reversible with treatment. This relies on ducts, blood vessels, and fat-storing cells). However, liver suppressing the production of the toxic substances in cells (hepatocytes) make up 80% of the liver tissue. Thus, the the intestine and is most commonly done with the majority of primary liver cancers (over 90%-95%) arises laxative lactulose or with non-absorbable antibiotics. In from liver cells and is called hepatocellular cancer or addition, the treatment of any underlying condition may carcinoma. Compared to other cancers, HCC is quite a rare improve the symptoms. In particular settings, such as acute tumor in the United States. In countries where hepatitis is liver failure, the onset of encephalopathy may indicate the not endemic, most malignant cancers in the liver are not need for a liver transplant . Ammonia, which is produced by primary HCC but metastasis (spread) of cancer from the body when proteins are digested, is one of the harmful elsewhere in the body, e.g., the colon. Treatment options of substances that is normally made harmless by the liver. Many HCC and prognosis are dependent on many factors but other substances may also build up in the body if the liver is especially on tumor size and staging. Tumor grade is also not working well. They can cause damage to the nervous important. High-grade tumors will have a poor prognosis, system. Hepatic encephalopathy may occur suddenly in while low-grade tumors may go unnoticed for many years, as people who previously had no liver problems when damage is the case in many other organs, such as the breast, where occurs to the liver20. a ductal carcinoma in situ (or a lob ular carcinoma in situ) Pathophysiology of Hepatic Encephalopathy: may be present without any clinical signs and without There are various explanations why liver dysfunction or correlate on routine imaging tests, although in some portosystemic shunting might lead to encephalopathy. In occasions it may be detected on more specialized imaging healthy subjects, nitrogen-containing compounds from studies like MR mammography. HCC may present the intestine, generated by gut bacteria from food, are with jaundice, bloating from ascites, easy bruising from transported by the portal vein to the liver, where 80–90% blood clotting abnormalities or as loss of appetite, is metabolised through the urea cycle and/or excreted Page 91 Sharma Nidhi et al. IRJP 2012, 3 (7) immediately. This process is impaired in all subtypes of Single dose of CCl4 (2.5ml/kg body wt, diluted with equal hepatic encephalopathy, either because the hepatocytes (liver volume of lipid paraffin; I.P.) to induced acute cells) are incapable of metabolising the waste products or hepatotoxicity dose administrated on 7 day. because portal venous blood bypasses the liver Thioacetamide induced hepatotoxicity: through collateral circulation or a medically constructed Thioacetamide has been used as an organic solvent in the shunt. Nitrogenous waste products accumulate in leather, textile, and paper industries, as an accelerator in the the systemic circulation (hence the older term "portosystemic vulcanization of buna rubber (synthetic polybutadiene), and encephalopathy"). The most important waste product as a stabilizer of motor fuel. Thioacetamide is an is ammonia (NH3). This small molecule crosses the blood- organosulfur compound. This white crystalline solid is brain barrier and is absorbed and metabolised by soluble in water and serves as a source of sulfideions in the theastrocytes, a population of cells in the brain that synthesis of organic and inorganic compounds. It is a constitutes 30% of the cerebral cortex. Astrocytes use prototypical thioamide. Thioacetamide, a selective ammonia when synthesising glutamine from glutamate. The hepatotoxic within a short period of time after the increased levels of glutamine lead to an increase in osmotic administration of the drug. It experiences an extensive pressure in the astrocytes, which become swollen. There is metabolism to acetamide and thioacetamide s-dioxide by the increased activity of the inhibitory γ-aminobutyric mixed function oxidase system . Acetamide does not have acid (GABA) system, and the energy supply to other brain liver necrotizing properties while thioacetamide S- oxide is cells is decreased. This can be thought of as an example of further metabolized to cytochrome P-450 mono oxygenase to brain oedema of the "cytotoxic" type21. Despite numerous sulfene, thioacetamide S-dioxide.the thioacetamide S- studies demonstrating the central role of ammonia, ammonia dioxide is a very extremely reactive compound. levels don't always correlate with the severity of the Thioacetamide is oxidized to a reactive metabolite that is encephalopathy; it is suspected that this means that more further oxidized to thioacetamide S- dioxide, which ammonia has already been absorbed into the brain in hose covalently to liver, macromolecules and initiates liver injury. with severe symptoms whose serum levels are relatively low. Mechanism of thioacetamide is due to the formation Other waste products implicated in hepatic encephalopathy of thioacetamide S-oxide which is responsible for the include mercaptans (substances containing a thiol group), amendment in cell permeability and the concentration of short-chain fatty acids and phenol. Numerous other Ca++ increases intracellular in nuclear volume and also abnormalities have been described in hepatic encephalopathy, obstructs mitochondrial activity which clues to cell death24. although their relative contribution to the disease state is Dose of Thioacetamide: 200mg/kg body weight uncertain. Benzodiazepine-like compounds have been administrated intraperitoneal twice weeks, for 8 weeks25. detected at increased levels as well as abnormalities in the Dose of thioacetamide: 600mg/kg body weight administrated GABA neurotransmission system. An imbalance between orally26. aromatic amino acids (phenylalanine, tryptophan and Galactosamine induced hepatotoxicity: tyrosine) and branched-chain amino acids (leucine, isoleucine D – Galactosamine (D-Gal) is a well-established and valine) has been described; this would lead to the hepatotoxicant, it induced a diffuse type of liver injury generation of false neurotransmitters (such octopamine and closely resembling human viral hepatitis and acute self- 2-hydroxyphenethylamine). Dysregulation of the serotonin limiting hepatitis with necrosis, inflammation and system, too, has been reported. Depletion of zinc and regeneration, resembling a drug- induced disease in human. accumulation of manganese may play a role. Inflammation The toxicity of D-Gal is mainly related to the depletion of elsewhere in the body may precipitate encephalopathy uridine pools that are associated with limited ribonucleic acid through the action of cytokines and bacterial (RNA) and protein synthesis, thus altering hepatocellular lipopolysaccharide on astrocytes22. function27. This mechanism of toxicity increases in cell DIFFERENT MODELS OF HEPATOTOXITY membrane porousness leading to cell death. Galactosamine CCl4 induced hepatotoxicity: decrease the bile flow and it’s gratified i.e. bile salts, cholic Carbon tetrachloride was formerly used for metal degreasing acid and deoxycholic acid. Dose of D- galactosamine: and as a dry-cleaning fluid, fabric-spotting fluid, fire- 400mg/kg, I.P.28. Single Dose of Galactosamine 800mg/kg extinguisher fluid, grain fumigant and reaction medium . I.P. administrated on 21th day of experiment29. Dose of Carbon tetrachloride (CCl4) induced liver damage has been Galactosamine 500mg/kg i.p. three times weekly for over a 30 lengthily used as an experimental model. CCL4 is used as a period of one to 3 month . model drug for the study of hepatotoxicity in acute and Alcohol induced hepatotoxicity: chronic liver failure. CCl4 is metabolized by CYP2E1, Liver is among the organs most susceptible to the toxic CYP2B and possibly CYP3A, to form the tri chloromethyl effects of ethanol. Alcohol consumption is known to cause radical, CCl3. This CCl3 radical can bind to cellular fatty infiltration, hepatitis and cirrhosis. Fat infiltration is a molecules damaging crucial cellular progression. This radical reversible phenomenon that occurs when alcohol replaces can also react with oxygen to form the tri-chlomethylperoxy fatty acids in the mitochondria. Hepatitis and cirrhosis may radical CCl3OO, a highly reactive species. The metabolites occur because of enhanced lipid peroxidative reaction during of CCl4 cause the hepatic injury in the CCl4 liver injury the microsomal metabolism of ethanol. It is generally model. Single dose of CCl4 to a rat produces centrilobular accepted that alcohol can induce in vivo changes in necrosis and fatty changes. The reaches its maximum membrane lipid composition and fluidity, which may concentration in the liver with in 3 hrs of administration23. eventually affect cellular functions. Among the mechanisms Dose of ccl4: 1 ml/kg carbontetrachloride, dissolve in olive responsible for effects of alcohol, an increase in hepatic lipid oil 1 : 1 ratio, administrated orally twice a week for over a peroxidation leads to alteration in membrane phospholipid period of 8 weeks. Dose of CCl4: 0.1to 3ml/kg I.P. for a composition. The effects of ethanol have been suggested to period on 7 day. CCl4 in liquid paraffin (30% v/v) 1ml/kg. be a result of the enhanced generation of oxy free radicals I.P. administered every 72 hours, for a period of 10days. during its oxidation in liver. The peroxidation of membrane Page 92 Sharma Nidhi et al. IRJP 2012, 3 (7) lipids results in loss of membrane structure and integrity. hydrazine, which is further metabolized to a toxic product by This results in elevated levels of glutamyl transpeptidase, a cytochrome P 450 leading to hepatotoxicity. Patients on membrane bound enzyme in serum. Ethanol inhibits concurrent rifampicin therapy have an increased incidence of glutathione peroxidase, decrease the activity of catalase, hepatitis. This has been postulated due to rifampicin-induced superoxide dismutase, along with increase in levels of cytochrome P 450 enzyme-induction, causing an increased glutathione in liver. The decrease in activity of antioxidant production of the toxic metabolites from acetyl hydrazine enzymes superoxide dismutase, glutathione peroxidase are (AcHz). Rifampicin also increases the metabolism of INH to speculated to be due to the damaging effects of free radicals isonicotinic acid and hydrazine, both of which are produced following ethanol exposure or alternatively could hepatotoxic. The plasma half life of AcHz (metabolite of be due to a direct effect of acetaldehyde, formed by oxidation INH) is shortened by rifampicin and AcHz is quickly of ethanol .Alcohol pre-treatment stimulates the toxicity of converted to its active metabolites by increasing the oxidative CCl 4 due to increased production of toxic reactive elimination rate of AcHz, which is related to the higher metabolites of CCl 4 , namely tri chloro-methyl radical by the incidence of liver necrosis caused by INH and rifampicin in microsomal mixed function oxidative system. This activated combination. Rifampicin induces hydrolysis pathway of INH radical binds covalently to the macromolecules and induces metabolism into the hepatotoxic metabolite hydrazine. peoxidative degradation of membrane lipids of endoplasmic Pharmacokinetic interactions exist between rifampicin and reticulum rich in polyunsaturated fatty acids. This lipid pyrazinamide in tuberculosis patients, when these drugs are peroxidative degradation of biomembranes is the principle administered concomitantly. Pyrazinamide decrease the cause of hepatotoxity31. Dose of ethanol 20% ethanol blood level of rifampicin by decreasing its bioavailability and (7.5g/kg body wt, 5 ml in the forenoon and 5ml in the increasing its clearance. Pyrazinamide, in combination with afternoon; oral) for six month. Dose of ethanol: 3g/kg body INH and rifampicin, appears to be associated with an weight, 30%v/v; p.o, for 20 days32. The initial dose of ethanol increased incidence of hepatotoxicity39. Dose of was 6g.kg-1.day-1 (solutions maximally containing 56% antitubercular drug (Isoniazid 7.5mg/kg, rifampicin 10mg/kg, alcohol), and the dose was progressively increased during pyrazinamide 35 mg/kg, p.o.) for 2 weeks40. Dose of week 1 to a maintenance dose of 8 g/kg/day that was antitubercular drug (isoniazid 27mg/kg/day, rifampicin continued for 5 more weeks33. 54mg/kg/day, pyrazinamide 135mg/kg/day p.o.) Paracetamol induced hepatotoxicity: administrated for 30 days, dose extrapolated from daily Paracetamol, a widely used analgesic and antipyretic drug, human dose using the conversion table based on body surface produces acute liver damage in high doses. Paracetamol area41. Dose of antitubercular drug (isoniazid and rifampicin administration causes necrosis of the centrilobular 200mg each/kg body weight/day, p.o.) for 45 days. hepatocytes characterized by nuclear pyknosis and Azathioprine induced hepatotxicity: eosinophilic cytoplasm followed by large excessive hepatic AZA is an important drug used in the therapy of autoimmune lesion. The covalent binding of N-acetyl- P- disorder and in preventing graft rejection. The nitro- benzoquinoneimine, an oxidative product of Paracetamol to conjugated double bond of imidazole ring of AZA is a sulphydryl groups of protein, result in lipid peroxidative Michael acceptor.AZA is cleaved in vitro to 6-MP non degradation of glutathione level and thereby, produces cell enzymatically by a nucleophillic attack of sulfhydryl groups necrosis in the liver. Dose of Paracetamol 1mg/kg p.o34. primarily GSH, on the b carbon in the activated double bond Single Dose of Paracetamol 3 g/kg p.o administrated on 10th AZA toxicity to rat hepatocytes was preceded by depletion of day of experiment35. Single dose of Paracetamol 2g/kg p.o GSH. Prior GSH depletion enhanced toxicity while administrated on 5th day of experiment36. Single dose of supplemental GSH was protective. In hepatocytes GSH is Paracetamol, 3g/kg p.o. administrated on 3rd day of consumed during metabolism of AZA to 6-MP.The experiment 37. mechanism of AZA toxicity to mitochondrial injury with Lithocholic acid induced hepatotoxicity: profound depletion of ATP and cell death by necrosis. Lipid The mechanism of hepatobiliary injury in the lithocholic acid peroxidation as well as altered levels of some endogenous progressively used model of cholestatic liver injury. The scavengers are taken as indirect in vivo reliable indices for etiology of LCA induced cholestasis in rat include the contribution of free radical generation and in turn biochemical alterations of the bile canalicular membrane. oxidative stress42. Due to the poor solubility of LCA the crystalline plugs Ranitidine induced epatotoxicity : develop in bile canaliculi and impaired transferring. Liver injury induced by ranitidine is due to its metabolite Administration of LCA can outcome in hepatocellular which may leads to hepatic oxidative damage and one of its necrosis with significant reductions in basolateral bile acid metabolite is generating immunoallergic reaction. It also uptake (Ntcp,Oatp1) and sinusoidal bile acid efflux produces a reaction as reflected by infiltration of hepatocytes transporters (Mrp3) increased. These changes in the liver with ranitidine dose of either 50 or 30 mg/kg. Severe represent an inherent toxicity of accumulating bile acids. inflammatory changes with collagenous septa beginning to Dose of lithocholic acid: single dose of 4µmol/100g body wt form after pronounced centrilobular and bridging necrosis in , administrated intravenously38. the parenchyma there was focal liver cell necrosis with some Antimicrobial drug induced hepatotoxicity: accumulation of histocytic elements and slight steatosis and Drug induced hepatotoxicity is a potentially serious adverse cholestasis. Portal tract shows fibrosis, bile duct proliferation effect of the currently used antitubercular therapeutic and infiltrate consisting of lymphocytes, plasma cells, regimens containing Isoniazid (INH), Rifampicin and polymorphs and eosinophils. Liver injury is manifested in Pyrazinamide. Adverse effects of antitubercular therapy are terms of increase in levels of serum aminotransferases, sometimes potentiated by multiple drug regimen. Thus, modesthepatic infiltration by both lymphocytes and though INH, Rifampicin and Pyrazinamide each in itself are eosinophils and slight focal hepatocellular necrosis also potentially hepatotoxic, when given in combination, their causes liver cholestasis associated with increased plasma toxic effect is enhanced. INH is metabolized to monoacetyl bilirubin andalkalin phosphatise43. Page 93 Sharma Nidhi et al. IRJP 2012, 3 (7) Mercury induced hepatotoxicity: alternative, more stable, BB 2,3-epoxide was found to Human activities play a major role in polluting the covalently bind soluble protein like haemoglobin. Drug environment by toxic and carcinogenic metal compounds. metaboliizing GSTs catalyze the sequestration of the reactive These are evidences that these metals by accumulating epoxides through conjugation to glutathione. The level of contaminate sources and food chain with their glutathione (GSH) conjugates excreted in the bile correlated compounds . Mercury and its compounds are widely used in with the BB dosage and the hepatotoxic effects. The epoxides industries and their hazards to animals have been are also hydrolyzed by the microsomal epoxide hydrolase and documented. Mercury is a transition metal and it promotes CYPs. The resulting bromophenols can be oxidized to the formation of reactive oxygen species (ROS) such as hydroquinones and conjugated to GSH. At high doses, hydrogen peroxides. These ROS enhance the peroxides and conjugation to the metabolites depletes the hepatic GSH pool, hydroxyl radicals. These lipid peroxides and hydroxyl radical and the intracellular protection against reactive oxygen may cause cell membrane damage and thus destroy the cell. species (ROS) and hazardous xenobiotic metabolites is lost. Mercury also inhibits the activities of free radical quenching This lead to a number of secondary events that damage the enzyme such as catalase, superoxide dismutase and cell, like lipid peroxidation, ATP depletion, mitochondrial glutathione peroxidise. Mercury causes cell membrane dysfunction, energy imbalance, and altered intracellular damage like lipid peroxidation which leads to the imbalance calcium levels49. Dose of bromobenzene (0.5, 2.0 and between synthesis and degradation of enzyme protein. The 5.0mmole/kg body weight, dissolved in corn oil, 40%v/v) excess production of ROS by mercury may be explained by administered orally for 10 – 12 weeks50. its ability to produce alteration in mitochondria by blocking CONCLUSION the permeability transition pore44. Dose of mercuric chloride : Hepatotoxicity implies chemical-driven liver damage. There 5mg/kg body weight, through intra peritoneal injection for are many chemical agents that cause hepatotoxicity and these twenty days. Mercuric chloride dose: 2mg/kg body weight, agents called hepatotoxins. These cause hepatotoxicity by the administrated orally for thirty days45. generation of free radicals and damage the liver cells and Lead induced hepatotoxicity : causes of many liver diseases. Mechanism of action of Many metals play important roles in the functioning of different chemical agents that cause liver damage and related enzyme, cell-signaling processes and gene regulation. Lead is liver diseases are discuss in this article. a blue-gray and highly toxic divalent metal that occurs REFERENCES: naturally in the earth’s crust and is spread throughout the 1. Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davron JT, Steven HB, Timothy M and Reish J. Results of a prospective study of acute environment by various human activities. Lead induced liver failure at 17 tertiary care centers in the United States. 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