A review on liver disorders and screening models of hepatoprotective agents

Eswar Kumar.A, et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-2(2) 2014 [136-150]
136
IJAMSCR |Volume 2 | Issue 2 | April - June - 2014
www.ijamscr.com
Review article
A review on liver disorders and screening models of
hepatoprotective agents
1
Eswar Kumar.A*,2
K.Susmitha, 3
B.Swathy,4
E.Ramu, 5
B.Venkatesh
1,2,3,4
College of Pharmacy, Palamuru University, Mahabubnagar, A.P. India.
5
Sri Venkateshwara College of Pharmacy, Hyderabad, India.
INTRODUCTION
LIVER
The liver is a vital organ present in vertebrates and
some other animals. It has a wide range of
functions, including detoxification, protein
synthesis, and production of bio chemicals
necessary for digestion. The liver is necessary for
survival; there is currently no way to compensate
for the absence of liver function long term,
although liver dialysis can be used short term.
This organ plays a major role in metabolism and
has a number of functions in the body, including
glycogen storage, decomposition of red blood cells,
plasma protein synthesis, hormone production, and
detoxification. It lies below the diaphragm in the
abdominal-pelvic region of the abdomen. It
produces bile, an alkaline compound which aids in
digestion via the emulsification of lipids. The
liver's highly specialized tissues regulate a wide
variety of high-volume biochemical reactions,
including the synthesis and breakdown of small and
complex molecules, many of which are necessary
for normal vital functions [1]
.
The various functions of the liver are carried out by
the liver cells or hepatocytes. Currently, there is no
artificial organ or device capable of emulating all
the functions of the liver. Some functions can be
emulated by liver dialysis, an experimental
treatment for liver failure
FUNCTIONS
Various functions of liver are as follows:
 A large part of amino acid synthesis
 The liver performs several roles in
carbohydrate metabolism:
 Gluconeogenesis (the synthesis of glucose
from certain amino acids, lactate or glycerol)
 Glycogenolysis (the breakdown of glycogen
into glucose)
 Glycogenesis (the formation of glycogen from
glucose)(muscle tissues can also do this)
 The liver is responsible for the mainstay of
protein metabolism, synthesis as well as
degradation
 The liver also performs several roles in lipid
metabolism:
o Cholesterol synthesis
o Lipogenesis, the production of
triglycerides (fats).
 The liver produces coagulation factors I
(fibrinogen), II (prothrombin), V, VII, IX, X
and XI, as well as protein C, protein S and
antithrombin.
 In the first trimester foetus, the liver is the
main site of red blood cell production. By the
32 nd week of gestation, the bone marrow has
almost completely taken over that task.
 The liver produces and excretes bile (a
yellowish liquid) required for emulsifying fats.
Some of the bile drains directly into the
duodenum, and some is stored in the
gallbladder.
 The liver also produces insulin-like growth
factor 1 (IGF-1), a polypeptide protein
hormone that plays an important role in
childhood growth and continues to have
anabolic effects in adults.
 The liver is a major site of thrombopoietin
production. Thrombopoietin is a glycoprotein
International Journal of Allied Medical Sciences
and Clinical Research (IJAMSCR)

www.ijamscr.com
~ 137 ~
hormone that regulates the production of
platelets by the bone marrow.
 The liver stores a multitude of substances,
including glucose (in the form of glycogen),
vitamin A (1–2 years' supply), vitamin D (1–4
months' supply), vitamin B12 (1-3 years'
supply), iron, and copper.
 The liver is responsible for immunological
effects- the reticuloendothelial system of the
liver contains many immunologically active
cells, acting as a 'sieve' for antigens carried to
it via the portal system.
 The liver produces albumin, the major osmolar
component of blood serum.
 The liver synthesizes angiotensinogen, a
hormone that is responsible for raising the
blood pressure when activated by renin, an
enzyme that is released when the kidney senses
low blood pressure
BREAKDOWN OF CHEMICAL
CONSTITUENTS
 The liver helps in the breakdown of insulin and
other hormones
 It breaks down hemoglobin, creating
metabolites that are added to bile as pigment
(bilirubin and biliverdin).
 It modifies toxic substances (e.g., methylation)
and most medicinal products in a process
called drug metabolism. This sometimes
results in toxicities, when the metabolite is
more toxic than its precursor. Preferably, the
toxins are conjugated to avail excretion in bile
or urine.
 The liver converts ammonia to urea.
DISORDERS OF LIVER
Liver disease (also called hepatic disease) is a
broad term describing any single number of
diseases affecting the liver. The liver supports
almost every organ in the body and is vital for
survival. Because of its strategic location and
multidimensional functions, the liver is also prone
to many diseases.[2]
 Hepatitis, inflammation of the liver, caused
mainly by various viruses but also by some
poisons (e.g. alcohol), autoimmunity
(autoimmune hepatitis) or hereditary
conditions. Diagnosis is done by checking
levels of Alanine transaminase
 Non-alcoholic fatty liver disease, a spectrum in
disease, associated with obesity and
characterized as an abundance of fat in the
liver; may lead to hepatitis, i.e. steatohepatitis
and/or cirrhosis.
 Cirrhosis is the formation of fibrous tissue in
the liver from replacing dead liver cells. The
death of the liver cells can be caused by viral
hepatitis, alcoholism or contact with other
liver-toxic chemicals. Diagnosis is done by
checking levels of Alanine transaminase and
Asparatine transaminase (SGOT).
 Haemochromatosis, a hereditary disease
causing the accumulation of iron in the body,
eventually leading to liver damage.
 Cancer of the liver (primary hepatocellular
carcinoma or cholangiocarcinoma and
metastatic cancers, usually from other parts of
the gastrointestinal tract).
 Wilson's disease, a hereditary disease which
causes the body to retain copper.
 Primary sclerosing cholangitis, an
inflammatory disease of the bile duct, likely
autoimmune in nature.
 Primary biliary cirrhosis, autoimmune disease
of small bile ducts.
 Budd-Chiari syndrome, obstruction of the
hepatic vein.
 Gilbert's syndrome, a genetic disorder of
bilirubin metabolism, found in about 5% of the
population.
 Glycogen storage disease type II, the build-up
of glycogen causes progressive muscle
weakness (myopathy) throughout the body and
affects various body tissues, particularly in the
heart, skeletal muscles, liver and nervous
system.
There are also many paediatric liver disease,
including biliary atresia, alpha-1 antitrypsin
deficiency, alagille syndrome, and progressive
familial intrahepatic cholestasis, to name but a few.
Alcohol-induced Liver Diseases
An alcohol-induced liver disease, as the name
implies, is caused by excessive consumption of
alcohol and is a common, but preventable, disease.
There are three primary types of alcohol-induced
liver disease, including the following.
(a) Fatty liver
Fatty liver is excessive accumulation of fat inside
the liver cells. Fatty liver is the most common
alcohol-induced liver disorder. The liver enlarged,
causing upper abdominal discomfort on the right
side.

138
(b) Alcoholic hepatitis
Alcoholic hepatitis is an acute inflammation of the
liver, accompanied by the destruction of individual
liver cell and scarring. Symptoms may include
fever, jaundice, an increased white blood cell
count, an enlarged, tender liver, and spider-like
veins in the skin.
(c) Alcoholic cirrhosis
Alcoholic cirrhosis is the destruction of normal
liver tissue, leaving non-functioning scar tissue.
Symptoms may include those of alcoholic hepatitis,
in addition to portal hypertension enlarged spleen,
as cites, kidney failure, confusion, or liver cancer.
Treatment of in alcoholic cirrhosis is abstinence
from alcohol and intake of an adequate wholesome
diet.
Symptoms
 Enlarged liver
 Fever
 Jaundice-yellowing of the skin and eyes
 Increased white blood cell count
 Spider-like veins in the skin
 Portal hypertension
 Enlarged spleen
 As cites- fluid build-up in the abdominal
cavity
 Kidney failure
 Confusion
Treatment of Alcohol-induced Liver
Diseases
The first treatment of alcohol-induced liver disease
is cessation of alcohol consumption. This is the
only way to reverse liver damage or prevent liver
injury from worsening. Without treatment, most
patients with alcohol-induced liver damage will
develop liver cirrhosis. Other treatment for
alcoholic hepatitis includes
(i) Nutrition
Doctors recommend a calorie-rich diet to help the
liver in its regeneration process. Dietary fat must be
reduced because fat interferes with alcohol
metabolism. The diet is usually supplemented with
vitamins and dietary minerals (including calcium
and iron).
Many nutritionists recommend a diet high in
protein, with frequent small meals eaten during the
day, about 5-6 instead of the usual 3. Nutritionally,
supporting the liver and supplementing with
nutrients that enhance liver function is
recommended. These include carnitine, which will
help reverse fatty livers, and vitamin C, which is an
antioxidant, aids in collagen synthesis, and
increases the production of neurotransmitters such
as nor epinephrine and serotonin, as well as
supplementing with the nutrients that have been
depleted due to the alcohol consumption.
Eliminating any food that may be manifesting as
intolerance and alkalizing the body is also
important. There are some supplements that are
recommended to help reduce cravings for alcohol,
including choline, glutamine, and vitamin C. As
research shows glucose increases the toxicity of
centrilobularhepatotoxicants by inhibiting cell
division and repair, it is suggested fatty acids are
used by the liver instead of glucose as a fuel source
to aid in repair; thus, it is recommended the patient
consumes a diet high in protein and essential fatty
acids, e.g. omega-3. Cessation of alcohol
consumption and cigarette smoking, and increasing
exercise are lifestyle recommendations to decrease
the risk of liver disease caused by alcoholic stress.
(ii) Drugs
Abstinence from alcohol intake and nutritional
modification form the backbone in the management
of alcohol liver diseases. Symptom treatment can
include: corticosteroids for severe cases,
anticytokines (infliximab and pentoxifylline),
propylthiouracil to modify metabolism and
colchicine to inhibit hepatic fibrosis.
(iii)Antioxidants
It is widely believedthat alcohol-induced liver
damage occurs via generation of oxidants Thus
alternative health care practitioners routinely
recommend natural antioxidant supplements like
milk thistle. Unfortunately, there is no valid clinical
data to show that milk thistle truly works.
(iv)Transplant
When all else fails and the liver is severely
damaged, the only alternative is a liver transplant.
While this is a viable option, liver transplant donors
are scarce and usually there is a long waiting list in
any given hospital. One of the criteria to become
eligible for a liver transplant is to discontinue
alcohol consumption for a minimum of six months.
Chronic Liver Disease/cirrhosis
Chronic liver disease is marked by the gradual
destruction of liver tissue over time. Several liver

www.ijamscr.com
~ 139 ~
disease falls under this category, including the
following:
(i) Cirrhosis of the liver
(ii) Fibrosis of the liver
Cirrhosis is the eighth leading cause of death in the
United States, according to the National Institute of
Diabetes and Digestive and Kidney Diseases
(NIDDK). Because of chronic damage to the liver,
scar tissue slowly replaces normal functioning liver
tissue, progressively diminishing blood flow
through the liver. As the normal liver tissue is lost,
nutrients, hormones, drugs, and poisons are not
processed effectively by the liver. In addition,
protein production and other substances produced
by the liver and inhibited.
Fibrosis is the growth of scar tissue due to
infection, inflammation injury, or even healing, the
over growth of scar tissue can occur in almost any
organ. Fibrosis in the liver can inhibit the organ’s
proper functioning.
Treatment of Liver Cirrhosis
Treatment depends on the type and stage of the
cirrhosis. Its aim is to stop the progress of the
cirrhosis, reversing (to whatever extent possible)
the damage that has already occurred, and treating
complications that are disabling or life-threatening.
Stopping or reversing the process requires removal
of the cause, as in the following cases:
 In cirrhosis caused by viral hepatitis: use
of experimental approaches that include
the use of drugs to improve immune
responses to viral infection (interferon) or
to help destroy the virus (anti-viral
compounds).
 In certain types of cirrhosis caused by
chronic hepatitis: corticosteroids are
indicated.
 In cirrhotic patients with jaundice: use of
supplemental fat soluble vitamins may be
helpful.
 In Wilson's disease: removal of excessive
copper.
 In hemochromatosis: removal of excess
iron.
 For patients with severe cirrhosis, a liver
transplant may be life-saving.
Congenital Liver Defects
Defects of the liver at birth usually affect the bile
ducts. Though rare, some congenital liver defects
include the following:
 Biliary Artesia-a condition in which the
bile ducts are absent or have developed
abnormally
 Choledochal cyst-a malformation of the
hepatic duct that can obstruct flow of bile
in infants.
Congenital liver defects that affect the flow of bile
share some common symptoms.
The following are the most common symptoms of
congenital liver defect. However, each individual
may experience symptoms differently. Symptoms
may include
 Jaundice- yellowing of the skin and eyes.
 Dark urine
 Pale stool
The symptoms of congenital liver defects may
resemble other medical conditions or problems.
Always consult the physician for a diagnosis.
Viruses induced liver diseases
Hepatitis is the inflammation of the liver, resulting
in the liver cell damaged and destruction. In
autoimmune hepatitis, the body’s own immune
system destroys the cells of the liver. It is a chronic
inflammatory liver disease with no known cause. It
is associated with a disorder called hyper
gammaglobuliemia. Hyper gamma globulinemia is
a disorder where there are too any circulating
protein antibodies in the blood. A chronic infection
or certain malignant blood diseases may cause
hyper gamma globulinemia. Autoimmune hepatitis
may resolve without the treatment in some
individual, but, for the majority of individuals, it is
chronic and can lead to cirrhosis and liver failure.
Autoimmune hepatitis may be classified as type 1
or type 2. Type 1 (classic) is the most common
form. It may occur at any age but usually affects
young women more than men. Also, other
autoimmune disorder can be associated with type 1
such as thyroiditis, Graves’s disease, and ulcerative
colitis. Type 2 generally affects girls between the
ages of 2-14, but does occur in adults.
Symptoms
The following are the most common symptoms of
autoimmune hepatitis. However, each individual
may experience symptoms differently. Symptoms
may include:
 Jaundice – yellowing of the skin and eyes.
 Fatigue
 Abdominal pain
 Severe acne
 Joint pain
 Joint swelling

140
 Cessation of menses
 Chest pain
 Diarrhea
 Fever
 Large abdomen due to large liver and
spleen
 Spider-like blood vessels in the skin
 Ascites-fluid build-up in the abdominal
cavity
Viruses induced hepatitis
There are six main types of the hepatitis virus that
have been identified, including the following:
Hepatitis A
This type of hepatitis is usually spread by fecal-oral
contact, or fecal-infected food and water, and may
also be spread by blood-borne infection (which is
rare).The following is a list of modes of
transmission for hepatitis A:
 Consuming food made by someone who
touched infected faces
 Drinking water that is contaminated by
infected feces (a problem
 Drinking water that is contaminated by
infected feces(a problem in developing
countries with poor sewage removal)
 Touching an infected person’s feces,
which may occur with poor hand washing
 Outbreaks may occur in large childcare
centers, especially when there are children
in diapers
 Residents of American Indian reservations
or Native Alaskan villages where hepatitis
A may be more common
 Sexual contact with an infected person. A
vaccine for hepatitis A has been developed
and is now available.
Hepatitis B
Hepatitis B has a wide range of clinical
presentations. It can be mild, without symptoms, or
it may cause chronic hepatitis and, in some cases,
can lead to full-blown liver failure and death.
Transmission of hepatitis B virus occurs though
blood and body fluid exposure such as blood,
semen, vaginal secretion, or saliva. Infants may
also develop the disease if they are born to a
mother who has the virus. Infected children often
spread the virus to other children if there is
frequent contact or a child has many scrapes or
cuts. The following describes persons who are at
risk for developing hepatitis B
 Children born to mother who have
hepatitis B (the illness may present up to
five years after the child is born)
 Children who are to mother who have
immigrated from a country where hepatitis
B is widespread such as southeast Asia
and China
 Persons who live in long-term care
facilities or who are disabled
 Persons who live in households where
another member is infected with the virus
 Persons who have a blood clotting
disorder such as hemophilia
 Persons who require dialysis for kidney
failure
 Persons who may participate in high-risk
activities such as intravenous (IV) drug
use and/or unprotected heterosexual or
homosexual sexual contact
 Persons who have a job that involves
contact with human blood
 Person may who received blood
transfusions or blood products before the
early 1990s
 A vaccine for hepatitis B does exist and is
now widely used for routine childhood
immunization. The centers for Disease
control and prevention (CDC) now
recommend that universal infant hepatitis
B vaccination should begin at birth except
in rare circumstances.
Hepatitis C
The symptoms of hepatitis C are usually mild and
gradual. Children often show no symptoms at all.
Transmission of hepatitis C occurs primarily from
contact with infected blood, but can also occur
from sexual contact or from an infected mother to
her baby. Although hepatitis C has milder
symptoms initially, it leads to chronic liver disease
in a majority of people who are infected. According
to the Centre for Disease Control and Prevention
(CDC), hepatitis C is the leading indication for
liver transplantation. With some cases of hepatitis
C, no mode of transmission can be identified.
The following describes persons who may be at
risk for contracting hepatitis C.
 Children are born to mothers who are infected
with the virus.
 Persons who have a blood clotting disorders
such as haemophilia and received clotting
factors before 1987.
 Persons who require dialysis for kidney failure.

www.ijamscr.com
~ 141 ~
 Individuals who received a blood transfusion
before 1992.
 Persons may participate in high – risk activities
such as intravenous drug use and/or
homosexual contact.
 There is no vaccine for hepatitis C. Persons
who are at risk should be checked regularly for
hepatitis C should be monitored closely for
signs of chronic hepatitis and failure
Hepatitis D
This form of hepatitis can only occur in the
presence of hepatitis B. If an individual has
hepatitis B and does not show symptoms, or shows
very mild symptoms, infection with D can put that
person at risk for full-blown liver failure that
progresses rapidly. Hepatitis D can occur at the
same time as the initial infection with B, or it may
show up much later. Transmission of hepatitis D
occurs the same way as hepatitis B, except the
transmission from mother to baby is common.
Hepatitis E
This form of hepatitis is similar to hepatitis A.
transmission occurs through faecal oral
contamination. It is a less common than hepatitis
A. Hepatitis E is most common in poorly
developed countries and rarely seen in the United
States. There is no vaccine for hepatitis E this time.
Hepatitis G
This is the newest strain of hepatitis and very little
is known about it. Transmission is believed to
occur through blood and is most commonly seen in
drug users, individuals with clotting disorders such
as haemophilia, and individuals who require
haemodialysis for renal failure. Often hepatitis G
shows no clinical symptoms and has not been
found to be a cause of acute or chronic hepatitis.
Drug induced hepatitis
Hepatitis is the inflammation of the liver resulting
in liver cell damage and destruction. Drug hepatitis
is rare and caused by toxic exposure to certain
medications, vitamins, herbal remedies or food
supplement. Usually, the toxicity occurs often
taking the causative agent for several months, or
from an over dose of a medication such as
acetaminophen. Usually if the agent is discontinued
once hepatitis is suspected and is rarely restarted
unless it is absolutely essential for treatment.
DISAESE SIGNS
The classic signs of liver damage include the
following
 Pale stools occur when stercobilin, a brown
pigment, is absent from the stool. Stercobilin is
derived from bilirubin metabolites produced in
the liver.
 Dark urine occurs when bilirubin mixes with
urine
 Bilirubin, when it deposits in skin, causes an
intense itch. Itching is the most common
complaint by people who have liver failure.
Often this itch cannot be relieved by drugs.
 Swelling of the abdomen, ankles and feet
occurs because the liver fails to make albumin.
 Excessive fatigue occurs from a generalized
loss of nutrients, minerals and vitamins.
 Bruising and easy bleeding are other features
of liver disease. The liver makes substances
which help prevent bleeding. When liver
damage occurs, these substances are no longer
present and severe bleeding can occur.[3]
DIAGNOSIS
The diagnosis of liver function is made by blood
tests. Liver function tests can readily pinpoint the
extent of liver damage. If infection is suspected,
then other serological tests are done. Sometimes,
one may require an ultrasound or a CT scan to
produce an image of the liver. Liver diseases may
be diagnosed by liver function tests, for example,
by production of proteins. Physical examination of
the liver is not accurate in determining the extent of
liver damage. It can only reveal presence of
tenderness or the size of liver, but in all cases,
some type of radiological study is required to
examine it.[4]
HEPATOTOXICITY
Chemicals that cause liver injury are called
hepatotoxins. The predominant type of liver disease
varies according to country and may be influenced
by local factors. The causative factors of liver
disorders include virus infection, exposure to or
consumption of certain chemicals. The substance
that injures the liver cells in some people and
results serious harm to the liver caused by drugs
and by the combination of drugs and other
substances is an important health problem.
Among various inorganic compounds producing
hepatotoxicity are arsenic, phosphorous, copper

142
and iron. The organic agents include certain
naturally-occurring plant toxins such as
pyrrolizidine alkaloids, mycotoxins and bacterial
toxins. The synthetic groups of organic compounds
are a large number of medicinal agents. In addition,
exposure to hepatotoxic compounds may be
occupational, environmental or domestic that could
be accidental, homicidal or suicidal ingestion.
More than 900 drugs have been implicated in
causing liver injury and it is the most common
reason for a drug to be withdrawn from the market.
Chemicals often cause sub clinical injury to liver
which manifests only as abnormal liver enzyme
tests. Drug induced liver injury is responsible for
5% of all hospital admissions and 50% of all acute
liver failures.
LIST OF HEPATOTOXIC COMPOUNDS
Various chemical agents that are hepatotoxic are as
follows
Table 1. CHEMICAL AGENTS
Compounds Examples
INORGANIC
AGENTS
Metals and metalloids: antimony, arsenic, beryllium, bismuth, boron, cadmium, chromium,
cobalt, copper, iron, lead, manganese, mercury, gold, phosphorous, selenium, tellurium,
thallium, zinc, hydrazine derivative, iodides [5, 6]
.
ORGANIC
AGENTS
Natural : Plant
toxins
Albitocin, cycasin, nutmeg, tannic acid, icterogenin, pyrrolidizines, saferole, indospicine.
Mycotoxins: Aflatoxins, cyclochlorotine, ethanol, luteoskyrin, griseofulvin, sporidesmin, tetracycline,
and other antibiotics.
Bacterial toxins: Exotoxins (C.diphtheria, Clostridium botulinus), endotoxins, ethionine.
Synthetic: Non-
medicinal
Haloalkanes and haloolephins, Nitroalkanes, Chloroaromatic compounds, Nitroaromatic
compound, organic amines, Azo compounds. Phenol and derivatives, various other organic
compounds
Various medicinal agents that are hepatotoxic are listed as follows:
Table 2. MEDICINAL AGENTS
Category of drugs Examples
1) Neuropsychotropics Hydrazine, tranylcypromine anticonvulsants, antidepressants.
2) Anti-inflammatory and anti-muscle spasm
agents
Cinchopen, cholchicine, ibuprofen, salicylates, indomethacin.
3) Hormonal derivatives and other drugs used
in endocrine disease
Acetohexamide, Azepinamide, Carbutamide, Tolbutamide.
4) Antimicrobials Clindamycin, novobiocin, penicillin, tetracycline,
sulfonamide, amodiaquine, isoniazid, rifampin.
5) Antineoplastic L-Asparaginase, azacytidine, methotrexate, 6-mercaptopurine,
chlorambucil, clavicin [7]
Various hepatotoxins can be classified according to their mechanism of action as follows:

www.ijamscr.com
~ 143 ~
Table 3. CLASSIFICATION OF HEPATOTOXINS AND
MECHANISM OF ACTION OF EACH GROUP
Category of
agents
Mechanism of action Histological
lesion
Examples
Intrinsic Toxicity
Direct Direct
Physiochemical destruction by
peroxidation of hepatocytes.
Necrosis and/or
steatosis
CCL4, phosphorus
Indirect cytotoxic Interference with hepatocellular
metabolic pathways
Steatosis or
necrosis
Ethionine, ethyl alcohol,
tetracycline[8]
Cholestatic Interference with bile excretory
pathways
Cholestasis duel
destruction
Methylene dianiline, anabolic
and contraceptive steroids[9]
Host Idiosyncrasy
Hypersensitivity Drug allergy Necrosis or
cholestasis
Chlorpromazine, phenytion,
sulfonamides.
Metabolic Production of pepatotoxic
metabolites
Necrosis or
cholestasis
Isoniazid, valproic acid [10]
Table 4: PATTERNS OF DRUG INDUCED CELL INJURY
Type of injury: Hepatocellular Homeostatic Mixed
ALT ≥ Twofold rise Normal ≥ Twofold rise
ALP Normal ≥ Twofold rise ≥ Twofold rise
ALT: ALP ratio High, ≥5 Low, ≤2 2-5
Examples[11]
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal contraception
Amitryptyline,
Enalapril
Carbamazepine
Sulphonamide
Phenytoin
Chemicals produce a wide variety of clinical and
pathological hepatic injury. Biochemical markers
(e.g. alanine transferase, alkaline phosphatase and
bilirubin) are often used to indicate liver damage.
Liver injury is defined as rise in either
(a) ALT level more than three times of upper limit
of normal (ULN),
(b) ALP level more than twice ULN, or
(c) Total bilirubin level more than twice ULN
when associated with increased ALT or ALP [12]
Liver damage is further characterized into
hepatocellular (predominantly initial Alanine
transferase elevation) and cholestatic (initial
alkaline phosphatase rise) types. However they are
not mutually exclusive and mixed type of injuries
are often encountered. Specific histo-pathological
patterns of liver injury from drug induced damage
are discussed below
Zonal Necrosis
This is the most common type of drug induced liver
cell necrosis where the injury is largely confined to
a particular zone of the liver lobule. It may
manifest as very high level of ALT and severe
disturbance of liver function leading to acute liver
failure. Causes include: Paracetamol, carbon
tetrachloride

144
Hepatitis
In this pattern hepatocellular necrosis is associated
with infiltration of inflammatory cells. There can
be three types of drug induced hepatitis:
(A) Viral hepatitis type picture is the commonest,
where histological features are similar to acute viral
hepatitis.
(B) In the focal or non specific hepatitis scattered
foci of cell necrosis may accompany lymphocyte
infiltrate.
(C) Chronic hepatitis type is very similar to
autoimmune hepatitis clinically, serologically as
well as histologically.
Causes
(a) Viral hepatitis like: Halothane, isoniazid,
phenytoin
(b) Focal hepatitis: Aspirin
(c) Chronic hepatitis: Methyldopa, diclofenac
Cholestasis
Liver injury leads to impairment of bile flow and
clinical picture is predominated by itching and
jaundice. Histology may show inflammation
(cholestatic hepatitis) or it can be bland without
any parenchyma inflammation. In rare occasions it
can produce features similar to primary biliary
cirrhosis due to progressive destruction of small
bile ducts (Vanishing duct syndrome).
Causes:
(a) Bland: Oral contraceptive pills, anabolic
steroid, androgens
(b) Inflammatory: Allopurinol, co-amoxiclav,
carbamazepine
(c) Ductal: Chlorpromazine, flucloxacillin
Steatosis
Hepatotoxicity may manifest as triglyceride
accumulation which leads to either small droplet
(micro vesicular) or large droplet (macro vesicular)
fatty liver. There is a separate type of steatosis
where phospholipids accumulation leads to a
pattern similar to the diseases with inherited
phospholipids metabolism defects (e.g. Tay-Sachs
disease)
Causes
(a) Micro vesicular: Aspirin (Reye's syndrome),
ketoprofen, tetracycline
(b) Macro vesicular: Acetaminophens,
methotrexate
(c) Phospholipidosis: Amiodarone, total parenteral
nutrition
Granola
Drug induced hepatic granulomas are usually
associated with granulomas in other tissues and
patients typically have features of systemic
vasculitis and hypersensitivity. More than 50 drugs
have been implicated.
Causes: Allopurinol, phenytoin, isoniazid, quinine,
penicillin, quinidine
Vascular lesions
They result from injury to the vascular
endothelium.
Causes: Venoocclusive disease: Chemotherapeutic
agents, bush tea
Peliosishepatis: anabolic steroid
Hepatic vein thrombosis: Oral contraceptives
Neoplasm
Neoplasms have been described with prolonged
exposure to some medications or toxins.
Hepatocellular carcinoma, angiosarcoma and liver
adenomas are the ones usually reported.
Causes: Vinyl chloride, combined oral
contraceptive pill, anabolic steroid, arsenic,
thorotrast.
SCREENING MODELS FOR
HEPATOTOXIC STUDIES
Various models needed for the screening of
hepatoprotectives can be classified as follows:
 In vivo models
 In vitro studies
These are briefly described as:
(a) In vivo models
(i) Toxic Chemicals-induced liver damage
A toxic dose or repeated doses of a known
hepatotoxin (carbon tetrachloride, paracetamol,
thioacetamide, isoniazid, alcohol, D-galactosamine,
allylalcohol, etc.) is administrated, to induce liver
damage in experimental animals. The test
substance is administered along with, prior to
and/or after the toxin treatment. If the
hepatotoxicity is prevented or reduced the test
substance is effective.
Liver damage and recovery from damage are
assessed by measuring serum marker enzymes,
bilirubin, histopathological changes in the liver,
biochemical changes in liver (E.g.: hydroxyproline,
lipid etc.) and bile flow. When liver is damaged

www.ijamscr.com
~ 145 ~
liver enzymes such as glutamate pyruvate
transaminase (GPT), glutamate oxaloacetate
transaminase (GOT) and alkaline phosphatase enter
into the circulation. An increase in the levels of
these marker enzymes in the serum is an indication
of liver damage. Other effects of induced liver
damage such as reduction of prothrombin synthesis
giving an extended prothrombin time and reduction
in clearance of certain substances such as
bromsulphthalein can be used in the evaluation of
hepatoprotective plants.
The hepatoprotective effect of a drug against
different hepatotoxins differs especially when the
mechanism of action of toxins are different.
Therefore, the efficacy of each drug has to be tested
against hepatotoxin which acts by different
methods [13]
.
ACETAMINOPHEN-INDUCED
HEPATOTOXICITY [14]
The analgesic acetaminophen causes a potentially
fatal, hepatic centrilobular necrosis when taken in
overdose. The initial phases of toxicity indicated
that acetaminophen was metabolically activated by
cytochrome P450 enzymes to a reactive metabolite
that depleted glutathione (GSH) and covalently
bound to protein. It was shown that repletion of
GSH prevented the toxicity. This finding led to the
development of the currently used antidote N-
acetylcysteine. The reactive metabolite was
subsequently identified to be N-acetyl-p-
benzoquinone imine (NAPQI) [15]
.It is detoxified by
glutathione (GSH) to form an acetaminophen-GSH
conjugate. After a toxic dose of acetaminophen,
total hepatic GSH is depleted by as much as 90%,
and as a result, the metabolite covalently binds to
cysteine groups on protein, forming
acetaminophen-protein adducts. This mechanism is
shown below
Fig. 4: Schematic representation depicting the role of metabolism in acetaminophen toxicity
Oxidative stress
Oxidative stress is another mechanism that has
been postulated to be important in the development
of acetaminophen toxicity. Thus, increased
formation of superoxide would lead to hydrogen
peroxide and peroxidation reactions by Fenton-type
mechanisms. It has been shown that NAPQI reacts
very rapidly with GSH (k1 = 3.2 × 104
M-1
s-1
at pH
7.0) [16]
, and there are a number of potential
mechanisms that have been suggested to play a
role. Under conditions of NAPQI formation
following toxic acetaminophen doses, GSH
concentrations may be very low in the centrilobular
cells, and the major peroxide detoxification
enzyme, GSH peroxidase, which functions very
inefficiently under conditions of GSH depletion [17]
,
is expected to be inhibited. In addition, during
formation of NAPQI by cytochrome P450, the
superoxide anion is formed, with dismutation
leading to hydrogen peroxide formation [18]
. Also, it
has been suggested that peroxidation of
acetaminophen to the semi Quinone free radical
would lead to redox cycling between the
acetaminophen and the semi Quinone. This
mechanism may lead to increased superoxide and
toxicity [19]
. However, it was found that the semi
Quinone reacted rapidly to form polymers and no
evidence for reaction of oxygen was observed [20]
.
A significant amount of evidence has pointed to the
potential involvement of oxidative stress in

146
acetaminophen toxicity. Nakae et al.(1990)
reported that administration of encapsulated
superoxide dismutase decreased the toxicity of
acetaminophen in the rat. Moreover, the iron
chelator, deferoxamine, has been shown to decrease
toxicity in rats [21]
. It was showed that deferoxamine
caused a delay in the rate of development of
acetaminophen toxicity in mice, but after 24 h, the
relative amount of toxicity was not affected[22]
.
Role of Kupffer Cells
Several laboratories have studied the role of
macrophage activation [22]
in acetaminophen
toxicity. Kupffer cells are the phagocytic
macrophages of the liver. When activated, Kupffer
cells release numerous signalling molecules,
including hydrolytic enzymes, eicosanoids, nitric
oxide, and superoxide. Kupffer cells may also
release a number of inflammatory cytokines,
including IL-1, IL-6, and TNF-αand multiple
cytokines are released in acetaminophen toxicity.
Hogaboam et al., (1999a, 2000) Bourdi et al.,
(2002a, b) Laskin et al. (1995) examined the role of
Kupffer cells in acetaminophen hepatotoxicity by
pre-treating rats with compounds that suppress
Kupffer cell function (gadolinium chloride and
dextran sulphate). These investigators reported that
rats pre-treated with these compounds were less
sensitive to the toxic effects of acetaminophen.
Similar effects were reported in the mouse.Goldin
et al. (1996) [23]
showed that treatment of mice with
liposome’s containing dichloro methylene di
phosphonate to knock out the Kupffer cells also
decreased acetaminophen toxicity. Similarly, pre-
treatment of mice with gadolinium chloride or
dextran sulphate decreased the toxic effects of
acetaminophen[24]
. These studies suggested a
critical role for Kupffer cells in the development of
acetaminophen hepatotoxicity.
CARBON TETRACHLORIDE INDUCED
HEPATOTOXICITY
Toxic injury of the liver induced by carbon
tetrachloride is a model system of hepatotoxicity.
Injury produced by CCl4 seems to be mediated by
reactive metabolite – trychloromethyl free radical
(CCl3
.)
formed by the hemolytic cleavage of CCl4
or by an even more reactive species
trichloromethylperoxy free radical (Cl3 COO.
)
formed by the reaction of CCl3
.
with O2
.
This
biotransformation is catalyzed by a cytochrome
p450 dependent monooxygenase.
CCl4 is reductively converted by P450 to the
trichloromethyl radical the fate of this radical is of
interest. First the radical add covalently to
unsaturated fatty acids, trichloromethyl fatty acids,
particularly of membrane phospholipids.
.
Recently these substituted fatty acids have been
noted to be partially resistant to replace from
endoplasmic reticular phospholipase A2.This seems
to be result of cross linking of trichloromethyl fatty
acid radical, which adds to double bond of other
adjacent fatty acids (link et. al)
The physiologic significance of this cross linking
on membrane structure and function may be of
great importance, particularly if these
phospholipids are transformed to other critical sites
in the cell. Besides covalent binding to lipid, the
cells can abstract an electron from unsaturated fatty
acids, yielding CHCl3 and or fatty acid
radical.Eitherthetrichloromethyl fatty acid radical
or the fatty acid radical can react with oxygen to
form peroxy radical, which initiates the lipid
peroxidation chain reaction.
The hepatoprotective study was carried out in adult
male Wistar rats (150-175 g). They were housed in
clean polypropylene cages and fed with
commercial rat chow and water ad libitum.

Eswar Kumar.A,etal / Int. J. of Allied Med. Sci. and Clin. Research Vol-1(1) 2013 [18-24]
www.ijamscr.com
~ 147 ~
A total of 30 animals were equally divided into 5 groups (n = 6 in each group). Group I (normal
control) and Group II (CCl4-treated control) were
given 0.9% saline (5 ml/kg, b.w.) for 9 days. Group
III and Group IV were pre-treated with AV (100
and 200 mg/kg, p.o., respectively) for 9 days, while
Group V was pre-treated with silymarin (25 mg/kg,
p.o.) for 9 days. Liver damage was induced in these
rats, except Group I, with 1:1 (v/v) mixture of CCl4
and olive oil (1ml/kg, s.c.) at Day 7 while, olive oil
(0.5 ml/kg, s.c.) was injected to Group I.The doses
of the test drug were selected on the basis of earlier
work in our laboratory.9 After 48 h of CCl4
treatment, i.e., on the 9th
day the animals were
sacrificed under anesthesia and blood was collected
for the assay of serum glutamate oxaloacetate
transaminase (SGOT), serum glutamate pyruvate
transaminase(SGPT) and serum alkaline
phosphatase (ALP) [25
THIOACETAMIDE INDUCED HEPATO
TOXICITY [26]
The ameliorative activity of aqueous extract of the
flesh of dates (Phoenix dactylifera L.) and ascorbic
acid on thioacetamide-induced hepatotoxicity was
studied in rats. Sixty male rats were divided into
six equal groups of 10. Two groups were controls,
one treated with thioacetamide and one with only
distilled water. Two groups received extract of
flesh Phoenix dactylifera and intraperitoneal (IP)
thioacetamide (400 mg/kg) either before or after
administration of flesh extract. Two groups
received ascorbic acid and intraperitoneal (IP)
thioacetamide (400 mg/kg b.w.t.) either before or
after administration of ascorbic acid. Liver damage
was assessed by estimation of plasma concentration
of bilirubin and enzymes activities of aspartate
aminotransferase (AST), alanine aminotransferase
(ALT), lactate dehydrogenase (LDH), γ
glutamyltransferase and alkaline phosphatase and
serum alpha fetoprotein and serum total
testosterone. Treatment with aqueous extract of
date flesh or by ascorbic acid significantly reduced
thioacetamide-induced elevation in plasma
bilirubin concentration and enzymes.
Thioacetamide (TA), originally used as a fungicide,
is a potent hepatotoxin which has been much
studied since the first report of its toxic properties
[27-32]
. Earlier literature [33-34]
suggests that an
obligate intermediate metabolite of TA that binds
to proteins with the formation of acetylimidolysine
derivatives [35]
is responsible for TA-induced
hepatotoxic effects (Fig. 1). TA stimulates DNA
synthesis and mitosis in the liver of rats at doses
that produce limited necrosis [36-37]
. The rise in
DNA synthesis induced by TA follows a time
sequence, which is similar to that seen after partial
hepatectomy [38]
. Rats treated with 50 mg TA/kg
body weight undergo hepatocellular proliferation as
suggested by 3
H-thymidine (3
H-T) incorporation,
which peaks 36 hr after administration.
Mechanism of thioacetamide TA) bio activation leading to hepatotoxicity. MFO, mixed-function oxidase
ISONIAZID INDUCED HEPATO
TOXICITY
Isoniazid (isonicotinic acid hydrazide [INH]) has
been used since 1952 as a front-line antimicrobial
for tuberculosis. It is commonly used alone for
prophylaxis of patients who have conversion of
their purified protein derivative (PPD) and normal
chest x-ray films, and it also is used in combination
with other medications for active disease. [39]
Some
studies suggest that people who are slow
acetylators are at greater risk of isoniazid
hepatotoxicity, suggesting that slow metabolism
results in diversion of isoniazid metabolism to an
alternate (e.g., cytochrome P-450-mediated)
pathway that may produce a toxic metabolite. This
latter interpretation is supported by observations
that drugs that induce cytochrome P-450 levels
(including rifampin, which is often prescribed with
isoniazid) appear to increase the risk of isoniazid
toxicity.

148
Isoniazid and its metabolites acetyl isoniazid,
hydrazine and monoacetylhydrazine were
investigated for generation of oxygen free radicals
during incubation with rat liver slices. Lipid
peroxidation was assessed by the thiobarbituric
acid reactive substances test using malonaldehyde
as the external standard, while hepatotoxicity was
assessed by histopathology studies. Malonaldehyde
formed in liver slices after 10 hours of incubation
with the drugs was 1.28 ± 0.24 nmol/mg for
isoniazid (control 1.12 ± 0.17 nmol/mg); 0.88 ±
0.45 nmol/mg for acetyl isoniazid (control 0.84 ±
0.42 nmol/mg); 1.43 ± 0.14 nmol/mg for
monoacetylhydrazine (control 1.10 ± 0.12
nmol/mg) and 1.36 ± 0.02 nmol/mg for hydrazine
(control 1.13 ± 0.04 nmol/mg). Histologically, all
slices exhibited hepatic necrosis by 4 hours.
However, hydrazine-induced hepatotoxicity was
characterized by nuclear hyperchromatsia,
karyolysis and karyohexis while mono
acetylhydrazine exhibited hydropickaryomegaly
only. Isoniazid and acetylisoniazid cytotoxicity
exhibited a mixture of the above features such that
it could be attributed to the two metabolites,
hydrazine and monoacetylhydrazine. In conclusion,
there was no evidence implicating oxygen free
radicals in isoniazid-induced hepatotoxicity [40]
GLUCOSAMINE INDUCED HEPATO
TOXICITY
Glucosamine is a popular dietary supplement either
alone or in combination with chondroitin sulphate
used to treat or prevent osteoarthritis. A small
number of reports of hepatitis in people taking
glucosamine or glucosamine and chondroitin
supplements have recently been made. D-
glucosamine, particularly at high concentrations,
causes an increase of UDP- N- acetyl-D
glucosamine and UDP- N- acetyl-D-galactosamine
in the liver [41]
.A reduction in uridine phosphate and
UDPhexose pools occurs as a consequence of D-
glucosamine metabolism. The extent of the uridine
phosphate trapping depends on the enzyme patterns
of the tissue concerned.
(ii) Anti-hepatitis Virus activity
At present, simple in vivo test systems are not
available to determine anti-hepatitis virus activity
in rodent models. However, duck and monkey
models have been introduced to test anti-hepatitis B
activity [42]
.
(iii) Choleretic activity
Techniques are available to collect bile by
cannulising the bile duct, in anaesthetised as well
as conscious animals, to study the effect of drugs
on the secretion.
(iv) Regeneration of hepatocytes
The effect of drugs on hepatocytes regeneration can
be tested by surgical removal of a portion of the
liver in experimental animals.
(b) In vitro studies
Fresh hepatocyte preparations and primary cultured
hepatocytes are used to study direct anti-
hepatotoxic activity of drugs. Hepatocytes are
treated with hepatotoxic and the effect of the plant
drug on the same is evaluated. The activities of the
transaminases released into the medium are
determined. An increase in the activity in the
medium indicates liver damage. Parameters such as
hepatocyte multiplication, morphology,
macromolecular synthesis and oxygen consumption
are determined.

Eswar Kumar.A,etal / Int. J. of Allied Med. Sci. and Clin. Research Vol-1(1) 2013 [18-24]
www.ijamscr.com
~ 149 ~
REFERENCES
[1] Maton, Anthea; Jean Hopkins, Charles William McLaughlin, Susan Johnson, MaryannaQuon Warner,
David LaHart, Jill D. Wright (1993). Human Biology and Health. Englewood Cliffs, New Jersey, USA:
Prentice Hall. ISBN 0-13-981176-1. OCLC 32308337
[2] Extraintestinal Complications: Liver Disease Crohn's& Colitis Foundation of America. Retrieved on
2010-01-22
[3] Liver Information Health Line. Retrieved on 2010-01-22
[4] Friedman, Scott E.; Grendell, James H.; Mc Quaid, Kenneth R. (2003). Current diagnosis & treatment
in gastroenterology.New York: Lang Medical Books/McGraw-Hill.pp. 664–679. ISBN 0-8385-1551-7.
[5] McNally, Peter F. (2006). GI/Liver Secrets: with STUDENT CONSULT Access. Saint Louis: C.V.
Mosby. ISBN 1-56053-618-7.
[6] Ostapowicz G, Fontana RJ, Schiødt FV, et al. (2002). "Results of a prospective study of acute liver
failure at 17 tertiary care centers in the United States". Ann. Intern. Med. 137 (12): 947–54.
PMID 12484709.
[7] Hyman J Zimmerman. Hepatotoxicity: The Adverse Effect of Drug and other chemicals on the Liver.
New York, Springer verlag 1978: 3-10.
[8] Ishak K G, Riddell R H. Pathology of Drug-Induced and Toxic Diseases. New York: Churchill
Livingstone; 1982.
[9] Alfred Goodman Gilman. The Pharmacological Basis of Therapeutics. New York: McGraw-Hill ;
2001.
[10]Nell Kaplowitz. Drug-Induced Hepatotoxicity. Current Hepatology 1986; 6: 242-43
[11]Mumoli N, Cei M, Cosimi A (2006). "Drug-related hepatotoxicity". N. Engl. J. Med.354 (20): 2191–3;
author reply 2191–3. doi:10.1056/NEJMc060733 PMID 16710915.
[12]Subramoniam A, Pushpangadan P. Development of Phytomedicines for liver diseases. Ind
JPharmacol. 1999; 31: 166-75.
[13]Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, and Brodie BB (1973) Acetaminophen-induced hepatic
necrosis. IV. Protective role of glutathione. J PharmacolExpTher 187: 211-217.
[14]Coles B, Wilson I, Wardman P, Hinson JA, Nelson SD, and Ketterer B (1988) The spontaneous and
enzymatic reaction of N-acetyl-p-benzoquinonimine with glutathione: a stopped-flow kinetic study.
Arch BiochemBiophys264:253-260.
[15]Nakamura W, Hosoda S, and Hayachi K (1974) Purification and properties of rat liver glutathione
peroxidase. BiochimBiophysActa358:251-261.
[16]Dai Y and Cederbaum AI (1995) Cytotoxicity of acetaminophen in human cytochrome P4502E1-
transfected HepG2 cells. J PharmacolExpTher 273: 1497-1505.
[17]deVries J (1981) Hepatotoxic metabolic activation of paracetamol and its derivatives phenacetin and
benorilate: oxygenation or electron transfer? BiochemPharmacol30:399-402.
[18]Potter DW, Pumford NR, Hinson JA, Benson RW, and Roberts DW (1989) Epitope characterization of
acetaminophen bound to protein and nonprotein sulfhydryl groups by an enzyme-linked
immunosorbent assay. J PharmacolExpTher 248: 182-189.
[19]Sakaida I, Kayano K, Wasaki S, Nagatomi A, Matsumura Y, and Okita K (1995) Protection against
acetaminophen-induced liver injury in vivo by an iron chelator, deferoxamine. Scand J Gastroenterol
30: 61-67.
[20]Schnellmann JG, Pumford NR, Kusewitt DF, Bucci TJ, and Hinson JA (1999) Deferoxamine delays
the development of the hepatotoxicity of acetaminophen in mice. ToxicolLett 106: 79-88.
[21]Laskin DL, Gardner CR, Price VF, and Jollow DJ (1995) Modulation of macrophage functioning
abrogates the acute hepatotoxicity of acetaminophen. Hepatology 21: 1045-1050.
[22]Blazka ME, Elwell MR, Holladay SD, Wilson RE, and Luster MI (1996) Histopathology of
acetaminophen-induced liver changes: role of interleukin 1 alpha and tumor necrosis factor alpha.
ToxicolPathol 24: 181-189.
[23]Goldin RD, Ratnayaka ID, Breach CS, Brown IN, and Wickramasinghe SN (1996) Role of
macrophages in acetaminophen (paracetamol)-induced hepatotoxicity. J Pathol179:432-435.

150
[24]Michael SL, Pumford NR, Mayeux PR, Niesman MR, and Hinson JA (1999) Pretreatment of mice with
macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen
and nitrogen species. Hepatology 30: 186-195.
[25]Bhattacharyya D, Mukherjee R, Pandit S, Das N, Sur TK. Hepatoprotective effect of Himoliv®, a
polyherbal formulation in rats. Indian J PhysiolPharmacol 2003;47:435-40.
[26]Mohamed Bastway Ahmed, Nabil Abdel-Salam Hasona* and Hanan Abdel-Hamid
SelemainDepartment of Chemistry, Biochemistry Branch, Faculty of Science, Beni-Suef University
Egypt.Iranian Journal of Pharmaceutical Research (2008), 7 (3): 193-201
[27]Fitzhugh OG, Nelson AA. Liver tumors in rats fed thiourea or thioacetamide. Science 108:626-628
(1948).
[28]Gallagher CH, Gupta DN, Judah JD, Rees KR. Biochemical changes in liver in acute thioacetamide
intoxication. J PatholBact 72:193-201 (1956)
[29]Gupta DN. Acute changes in the liver after administration of thioacetamide. J PatholBact 72:183-192
(1956).
[30]Trennery PN, Waring RH. Early changes in thioacetamide induced liver damage. ToxicolLett 19:299-
307 (1983).
[31]Becker V, Walter S. Die wirking von thioacetylverbindungen auf das leberparenchymim
Tierexperiment. ActaHepato-Solenol 12:129-140 (1965).
[32]Ammon R, Berninger H, Haas HJ, Landsherg I. Thioacetamidesulfoxid, einstoffwechselprodukt des
thioacetamids. ArzneimittelForschung 17:521-523 (1967).
[33]Vadi HV, Neal RA. Microsomal activation of thioacetamide-S-oxide to a metabolite(s) that covalently
binds to calf thymus DNA and other polynucleotides. Chem-Biol Interact 35:25-38 (1981).
[34]Dyroff MC, Neal RA. Identification of the major protein adduct formed in rat liver after thioacetamide
administration. Cancer Res 41:3430-3435 (1981).
[35]Marley CGD, Boyer JL. Stimulation of hepatocellular proliferation by a serum factor from
thioacetamide treated rats. BiochimBiophysActa 477:165-176 (1977).
[36]Diaz-Gil JJ, Sanchez G, Santamaria L, Trilla C, Esteban P, Escartin P, Gea T. A liver DNA synthesis
promoter induced in rat plasma by injection of dimethylnitrosamine (DMNA) or thioacetamide. Br J
Cancer 55:599-604 (1987).
[37]Bucher NLR, Malt RA. Regeneration of liver and kidney, 1st ed. Boston:Little, Brown and Co.,
1973;55-72.
[38]Reddy J, Chiga M, Svoboda D. Initiation of division cycle of rat hepatocytes following a single
injection of thioacetamide. Lab Invest 20:405-411 (1969).
[39]RoyPD, Majumder M, Roy B. Pharmacogenomics of anti-TB drugs-related hepatotoxicity. Pharmaco-
genomics. Mar 2008;9(3):311-21. [Medline]
[40]Walubo, A., Smith, P., Folb, P.I.Methods Find Exp.Clin.Pharmacol 1998, 20(8):649ISSN03790355
Copyright1998ProusScienceCCC:03790355DOI:10.1358/mf.1998.20.8.487491
************************

A review on liver disorders and screening models of hepatoprotective agents

More Related Content

What's hot (19)

Similar to A review on liver disorders and screening models of hepatoprotective agents (20)

More from pharmaindexing (20)

Recently uploaded (20)

A review on liver disorders and screening models of hepatoprotective agents