Abstract
Coconut
water was investigated for its possible effect on the acetaminophen
(paracetamol) overdosage-induced hepatotoxicity in three groups of albino
Wistar rats. Administration of the minimum toxic dose of paracetamol (150mg/kg
body weight) to animals (group II) produced significantly (P0.05)
higher levels of alanine aminotransferase (ALT) and alkaline phosphatase (ALP)
activities when compared to the control group (group I). There was however no
significant (P0.05) aspartate aminotransferase (AST) activity.
Significantly (p
CHAPTER ONE
1.0 INTRODUCTION
From the era of
ancient man, there has always been interaction between man and his environment
and this had led to the establishment of relationships. Such relationship
could either be beneficial or detrimental. Man has been able to gain
experiences that have helped him harness the benefits of such relationships as
well as handle the negativities associated with it, among which are poisonous
interactions like bites, stings, poisonous plants eaten as food etc, all of
which result in disease. In a bid to find remedy, he has also always had
to fall back on his immediate environment constituted largely by plants and
plant products. The ancient man had little knowledge of the medicinal
value of natural products, which he discovered by trial and error or by
accidental observations of the discriminatory use of these plants by
animals. Thus, by testing herbs, people began to acquire some rudimentary
knowledge about medicine and pharmacology1. In West Africa, treatment
has been provided by native doctors whose materia medica composed mainly
of plants but sometimes involved animals and animal products2.
Quite a number of
plants have been explored as antitoxins. Among the Anglo-saxon herbalists
of the 10th Century, nettle (Urtica diordica) was used to
counteract poisons and bites of dogs and bats. The seeds and flowers were also
used for chills and fevers. In some parts of Africa, the decoction of the
peeled branches of Spartium junceum (Spanish broom) was used as antidote
against viper venom. Herbs like burdock, juniper, kelp, alfafa, dandelion,
fennel and garlic also had widespread uses in counteracting metal
poisoning. In traditional African practice, Allium cepa (onion)
has been used to neutralize toxins resulting from scorpion stings. Modern
science has proved the efficacy of many of the preparations used in
ethnopharmacology and folk medicare. Pamplona-Roger3 for instance,
has reported that onions stimulate metabolic and detoxification function of the
liver. Morton4 reported the use of sugar made from the sap of
Borassus palms (Arecaceae), a coconut-like fruit, to counteract
poisoning in addition to its prescription in liver disorder.
Cocus nucifera
(coconut) is traditionally recognised for its medicinal properties5
among several other uses6. The use of coconut water to counteract
poisons is a common practice in Africa as well as India7. It has
severally been used as an immediate remedy for drug overdosage. This study was
thus designed to provide a scientific basis with which to validate the claims
of this practice. It was also designed to investigate the safety of this
practice by testing the effect of coconut water on the liver of patients who
have taken overdose of paracetamol.
1.2 Toxicity
Toxicity
is the degree to which a substance is able to damage an exposed organism. The
study of the adverse effects of chemicals on living organisms; the study of
symptoms, mechanisms and treatments is called toxicology. Toxicity can refer to
the effect on a whole organism, such as an animal, bacterium or plant, as well
as the effect on a substructure of the organism, such as a cell (cytotoxicity)
or organ (organotoxicity), such as the liver (hepatotoxicity).
Toxicity
may be acute, sub-acute/sub-chronic or chronic.
Acute
Toxicity
Acute
toxicity looks at lethal effects following oral, dermal or inhalation exposure
to a toxin. In acute toxicity, there is a single exposure to a toxicant which
may result in severe biological harm or death; acute exposures are usually characterised
as lasting no longer than twenty four (24) hours. The information on acute
systemic toxicity generated by the acute toxicity testing is used in hazard
identification and risk management in the context of production, management,
and utilization of chemicals.
The
LD50 value, (the statistically derived dose that, when administered in an acute
toxicity test, is expected to cause death in 50% of the treated animals in a
given period), is currently the starting point for toxicological classification
of chemicals. Laboratory mice and rats are the species typically selected for a
classic LD50 study. Often both sexes must be used for regulatory purposes. When
oral administration is combined with parenteral, information on the
bioavailability of the tested compound is obtained (Walum, 1998).
Efforts
have also been made to develop in vitro systems; e.g., it has been
suggested that acute systemic toxicity can be broken down into a number of
biokinetic, cellular, and molecular elements, each of which can be identified
and quantified in appropriate models. The various elements may then be used in
different combinations to model large numbers of toxic trial to predict hazard
and classify compounds.
1.2.1 Chronic Toxicity
Chronic
exposure to a toxin is over an extended period of time, often measured in
months or years, and can cause irreversible side effects. Two distinct
situations need to be considered:
Prolonged
exposure to a substance, for example ingestion of too much alcohol on a regular
basis; Alcohol has a short half-life but if ingested on a regular basis,
results in health hazards); Prolonged internal exposure because a substance
remains in the body for a long time; for example if a person were to ingest
radium, much of it would be absorbed into the bones where it would exert a
harmful effect in the blood cell-forming bone marrow.
Periods
of exposure between acute and chronic could be referred to as sub-acute or
sub-chronic.
A
central concept of toxicology is that effects are dose dependent; even water
can lead to water intoxication when taken in large enough doses, whereas for
even a very toxic substance such as snake venom, there is a dose below which
there is no detectable toxic effect.
Drugs
that exert their toxic effects on the liver may do so through the hepatic
production of a toxic metabolite. Drug toxicity may occur in all individuals
exposed to a sufficient concentration of a particular drug. A drug may even be
toxic in some individuals at concentrations normally tolerated by most patients
prescribed the drug. This phenomenon is known as idiosyncratic drug toxicity,
and may be due to a genetic or immunologic cause.
1.2.2 Target organ Toxicity
The
extent to which an organ is susceptible to toxicity varies from organ to organ.
For example the kidneys and liver are more highly vascularised making them more
susceptible to toxicity than the bone tissues.
Blood Toxicity
Blood
which forms the main medium of transport in the body is a very important
tissue. It serves to transport many drugs and xenobiotic. Since all foreign
compounds are distributed via the bloodstream, the various components, cellular
and non-cellular, are initially exposed to significant concentrations of toxic
compounds (Timbrel, 2009).
Some
plant materials when ingested either in the raw state or their extract, have
been reported to cause anaemia which may result from sequestration of red blood
cell in the spleen, impaired red cell production or primary bone marrow
dysfunction (Cheeke, 1998).
Damage to and
destruction of the blood cells results in a variety of consequences such as a
reduction in the oxygen-carrying capacity of the blood if the cells affected
are the red blood cells. The assessment of blood is relevant to the evaluation
of risks since the haematological system carries a higher predictive value for
toxicity in humans (90%) (Olson et al., 2000).
1.2.3 Liver Toxicity
The
liver is the main organ of metabolism and energy production. Its other main
functions include: bile production, storage of iron, vitamins and trace
elements, detoxification, conversion of waste products for excretion by the
kidneys.
The
liver is functionally divided into two lobes, right and left. The external
division is marked on the front of the liver by the falciform ligament, which
joins the coronary ligament at the superior margin of the liver. It receives
30% of the resting cardiac output and acts as a giant chemical processing plant
in the body. These chemical reactions, called metabolism, are central in the
regulation of body homeostasis. It also stores nutrients and other useful
substances, as well as detoxifying or breaking down harmful compounds. These
can then be excreted from the body in bile via the liver; in urine via the
kidney, or by other means. The liver metabolises both beneficial and harmful
substances. It has an immense task of detoxification of xenobiotics,
environmental pollutants and chemotherapeutic agents. Thus, the liver is
subjected to a variety of diseases and disorders (which may be acute or
chronic) caused by these agents or their metabolites. Acute and chronic liver
diseases constitute a global concern, but medical treatments for these diseases
are often difficult to handle and have limited efficacy (Kim et al.,
2009).
The liver performs a
variety of important host defense and metabolic functions that include
synthesis of acute-phase proteins, gluconeogenesis, detoxification, and
clearance of endogenous mediators, as well as secretion of pro-inflammatory
cytokines (Pastor et al., 1995). It is a unique organ in the sense that
a significant loss of liver cells due to drug toxicity or other insults can be
overcome by regeneration (Mehendale, 2005).
Several plant
extracts have been examined for use in a wide variety of liver disorders, Glycosmis
pentaphylla protects membrane integrity in mice hepatocytes (Nayak et
al., 2011), Silybum marianum (source of silymarin) is a
chemo-preventive agent that exhibits antitumor activity against human tumors in
rodents (Agarwal et al., 2006) just to mention a few; while others have
been reported to cause injury to the liver. For example, Artemisia macivera Linn
which is a traditional antimalarial in Nigeria is reported to be hepatotoxic in
rats at the onset of treatment, especially at higher doses (Atawodi et al.,
2011) and several cases of hepatotoxic side effects of green tea have been
reported (Rohde et al., 2011).
1.2.4 Drug Metabolism in liver
The
ability of humans to metabolize and clear drugs is a natural process that
involves the same enzymatic pathways and transport systems that are utilized
for normal metabolism of dietary constituents. The human body identifies almost
all drugs as foreign substances (xenobiotic) and subjects them to various
chemical processes to make them suitable for elimination. This involves
chemical transformations to reduce fat solubility and to change biological
activity. Although almost all tissues in the body have some ability to
metabolise chemicals, smooth endoplasmic reticulum in the liver is the
principal metabolic clearing house for both endogenous chemicals (example,
fatty acids, and steroid hormones) and exogenous substances like drugs
(Blumenthal et al., 2006).
Drug metabolism is
usually divided into two phases: phase 1 and phase 2. Phase 1 reaction, in
which enzymes carry out oxidation, reduction, or hydrolytic reactions, is
thought to prepare a drug for phase 2 in which enzymes form a conjugate of the
substrate (the phase 1 product). These processes tend to increase water
solubility of the drug and can generate metabolites which are more chemically
active and potentially toxic. Most of phase 2 reactions take place in the
cytosol and involve conjugation with endogenous compounds via transferase
enzymes. Chemically active products from phase 1 are made relatively inert and
suitable for elimination by the phase 2 step (Liston et al., 2001).
Interactions
are not only experienced with drugs: constituents of food may also take part in
drug interactions. An example of this effect is the well-known inhibitory
action of grapefruit juice on some cytochrome P450 isoenzymes, which was
discovered rather by chance (Anzenbacher and Anzenbacherová, 2001). In this
case, the in vivo effect can be quite dramatic with a single glass of
grapefruit juice resulting in fivefold increase in the values of the main
pharmacokinetic parameters such as the Cmax and Area under pharmacokinetic
curve (AUC) for dihydropyridine beta-blocking agents (e.g. nifedipine)
(Anzenbacher and Anzenbacherová, 2001).
A group of enzymes
located in the endoplasmic reticulum, known as cytochrome P-450 is the most
important family of metabolizing enzymes in the liver.
1.3 AIMS OF RESEARCH
The aim of this
research is to investigate the effect of coconut water on the liver of patients
who have taken overdose of paracetamol.
1.4 SIGNIFICANCE OF RESEARCH
The study will help
in examine the effect coconut water has on the liver. It will also investigate
the effect of coconut water in reducing the side effects as a result of
overdosage of paracetamol which is also known as acetaminophen.