THE CARICA PAPAYA LEAF IN MODERN THERAPY – Efficacy as antiparasitic, antiplasmodial, antiviral and anti-cancer agent

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THE CARICA PAPAYA LEAF IN MODERN THERAPY – Efficacy
as antiparasitic, antiplasmodial, antiviral and anti-cancer
agent
Beldeu Singh
Key words: antiviral, antimicrobial, antiplasmodial, antioxidant, carpaine,
immunostimulant, cyanogen, thiocyanate, dengue, malaria, thrombocytopenia
Abstract
Papaya has been used widely in traditional medicine for many ailments. It is
used in Ayurveda. There is information of the use of papaya leaves traditional
Malay medicine. The fruit, seeds and leaf contain many biologically active
compounds and antioxidants. Research showed very significant broad
spectrum antimicrobial activity. The fruit juice and leaf extract have been
demonstrated to have a wide variety of properties including anticancer,
antioxidative, anti-inflammatory, anti-bacterial, nephroprotective,
hepatoprotective, hypoglycemic and hypolipidemic effects, and anti-sickling
effect in sickle cell disease. Daily consumption of papaya (Carica papaya)
leaves as greens and herbal infusion is common in some parts of Indonesia
as a means for preventing malaria. Researchers have now become more
interested in phytochemicals from edible plants about natural products of
higher plants due to novel source of antimicrobial agents. The aqueous
extract of papaya leaf has also been shown to significantly decreased blood
glucose levels in diabetic rats and lowers blood pressure. In recent times,
there have been heated discussions and debates on the efficacy of papaya
leaves in management of dengue fever especially in increasing platelet count
in dengue patients with low platelet count and in those who develop
hemorrhagic dengue fever, including concerns about its cyanogenic
compound – cyanogenic glycoside.
Introduction
Papaya has been used widely in traditional medicine for many ailments: the
juices for warts, corns, cancers, tumors, hemorrhoids, diuretic, improving skin
condition, relief from asthma, healing from burns and scalding in combination
with aloe vera etc. Its young leaves, shoots and fruits are cooked as a
vegetable. This has drawn considerable interest from researchers in bio-
medical science and governments interested in developing a safer
pharmacopeia (that may be integrated with drug therapy). Papaya is used in
the beer industry, leather industry, in facial creams, etc.1

Previous phytochemical screening of papaya leaves showed the presence of
alkaloids, carbohydrates, saponins, glycosides, proteins and amino acids,
phytosterol, phenolic compounds, flavonoids, terpenoids and tannins in
different extracts. The presence of phytosterol in papaya leaf was very
prominent in all extracts. The saponins, glycosides, proteins and amino acids,
flavonoid, terpenoids showed greater intensity of their presence in methanol.
Emerging new information
Clinical trials have given light to the abilities papaya leaf tea has in reducing
the risk of certain cancers. This is because components in the papaya leaf
can help inhibit the cellular growth of tumors and may actually cut off the
blood supply to tumors. Evidence has shown that the juice from the leaf
prevents abnormal cell growth and can interfere with the growth of tumors.
Researchers observed significant growth inhibitory activity of the CP extract
on tumor cell lines. Since, papaya leaf extract can mediate a Th1 type shift in
the human immune system, it may potentially provide the means for the
treatment and prevention of selected human diseases such as cancer, various
allergic disorders, and may also serve as immunoadjuvant for vaccine
therapy.2 The aqueous extract of papaya flesh (0.01% - 4% v/v) treated with
breast cancer cell line MCF7 revealed significant inhibition of cell
proliferation.3 There is also demonstration of chemopreventive activities of
papaya seed products. The flavonoid-enriched benzene fraction of the
aqueous extract exerted its anticancer properties in vitro through
cytoprotection, antioxidative and antiinflammatory mechanisms and
genoprotection in response to isocyanate-induced carcinogenicity.4 Benzyl
glucosinolate (BG) in the pulp and the seed shows anti-cancer activity upon
hydrolysis. BG also can be produced in the pulp of papaya and it is stored in
the seed after the fruit has been matured. The hydrolysis product of BG has
certain cancer-prevention anti-cancer activities for human.5
Benzyl isothiocyanate is found in the seeds. The n-hexane extract of the
papaya seed homogenate was highly effective in inhibiting superoxide
generation and apoptosis induction in HL-60 cells.6 Research indicates that
benzyl isothiocyanate is the predominant or sole anthelmintic agent in papaya
seed extracts regardless of how seeds are extracted.7 These findings show
that a new compliment can be made available for better anticancer therapy by
combining with leaf extracts from certain other edible plants.
In addition, trials are underway which study the use of papaya leaf extract with
those undergoing chemotherapy in order to enhance the cancer fighting
properties. Eating papaya together with certain other fruits and drinking
papaya leaf tea has therapeutic value in relief for digestive discomforts and

abdominal pains, including those associated with micro-parasitic infections.
Papaya and its dried seeds has been used in traditional medicine used for
preventing and treating gastrointestinal tract disorders associated with
intestinal parasite infections and as a diuretic. Papaya leaf extracts have been
investigated for treatment of dengue fever which has reached alarming
proportions in the past few years.
The alkaline and alcoholic extracts of P. americana and C. papaya produced
significant reduction in the number of sickle cells.8 The wide range of health
benefits are due to the broad range of phytochemicals and antioxidants in
papaya. Papaya leaf contains nutrients and antioxidants such as B-vitamins
for vitality and enhanced mood, vitamins A, C, D and E and calcium which is
useful in preventing osteoporosis and improving calcium signaling in cells and
increases energy molecules (ATP) output in the mitochondria. Papaya leaf
also contains 50 or more different amino acids such as: threonine, glutamate
acid, glycine, valine, leucine, phenylalanine, lysine, tryptophan, cysteine,
histidine, tyrosine, alanine, proline, aspartate, etc., Together, these
phytochemicals in this edible resource have anti-aging effects and are used in
cosmetics for achieving youthful and healthy looking skin. It has strong free-
radical scavenging activity and anti-inflammatory properties. Naturally, it also
improves immune function and it is an important component in clinical
nutrition. When incorporated into the diet, it results in a very healthy life style.
Effect on blood pressure, antimicrobial activity, stroke,
thrombocytopenia
Daily consumption of papaya (Carica papaya) leaves as greens and herbal
infusion is common in some parts of Indonesia as a means for preventing
malaria. The anti-plasmodial activity of the leaf extracts and of the main
alkaloid carpaine were recently confirmed. Carpaine concentration in dry
leaves was found to range from 0.02 to 0.31% with no obvious dependence
on geographic origin and leaf maturity9 which indicates it is not related to
cyanogenic compounds as the concentration of these compounds decrease
dramatically in mature leaves.
Carpaine is the major alkaloid found in the papaya plant. Carpaine slows the
heart rate in humans and thus reduces blood pressure. Its action is similar to
digitalis, the drug prescribed for heart patients.10 The alkaloid is reported to be
able to kill worms and amoeba. It has a broad spectrum of anti-bacterial
properties.11 Another useful compound not readily found in the plant kingdom
is Fibrin. It reduces the risk of blood clots and improves the quality of blood
cells, optimizing the ability of blood to flow through the circulatory system.
Fibrin is also important in preventing stroke.12

The decoction of Carica papaya (Linn.) leaves is used in folklore medicine in
certain parts of Malaysia and Indonesia for the treatment of different types of
thrombocytopenia associated with diseases and drugs. There are several
scientific studies carried out on humans and animal models to confirm the
efficacy of decoction of papaya leave for the treatment of disease induced and
drug induced thrombocytopenia, however very little is known about the bio-
active compounds responsible for the observed activity. A study was
conducted to identify the active phytochemical component of Carica papaya
(Linn.) leaves decoction responsible for anti-thrombocytopenic activity in
busulfan-induced thrombocytopenic rats. Two different phytochemical groups
were isolated from decoction of Carica papaya leaves: phenolics, and
alkaloids. Out of these, only the alkaloid fraction showed good biological
activity. Carpaine was isolated from the alkaloid fraction and exhibited potent
activity in sustaining platelet counts up to 555.50±85.17×109 /L with no acute
toxicity. This study scientifically validates the popular usage of decoction of
Carica papaya leaves and it also proves that alkaloids, particularly carpaine
present in the leaves to be responsible for the antithrombocytopenic activity.13
Treatment of ulcers
An ulcer is basically an inflamed break in the skin or the mucus membrane
lining the alimentary tract. Ulceration occurs when there is a disturbance of
the normal equilibrium caused by either enhanced aggression or diminished
mucosal resistance. About 19 out of 20 peptic ulcers are duodenal. Gastric
ulcers, found in the stomach wall, are less common. The gastric mucosa is
continuously exposed to potentially injurious agents such as acid, pepsin, bile
acids, food ingredients, bacterial products (Helicobacter pylori) and drugs.
Papaya fruit and leaf can be used to treat ulcers because of its anti-
inflammatory and anti-bacterial properties and more research is required in
this therapy.
The fruit contains many biologically active compounds. Two important
compounds are chymopapain and papain, which are widely known as being
useful for digestive disorders and disturbances of the gastrointestinal tract
because the fruit and seeds have anthelmintic and anti-amebic activities. The
main chemical components are papain, chymopapain, pectin, carposide,
carpaine, pseudocarpaine, dehydrocarpines, carotenoids, crypto glavine, cis-
violaxanthin and antheraxanthin. The leaves of the papaya tree are useful too
as they are often used for dressing wounds and injuries.14
Papain regulates the expression of replicase polyproteins. It is a strong
digestive enzyme and useful in serious digestive disorders such as bloating
and chronic indigestion. A unique ability of papain is to break down protein
and convert a portion of it into arginine because arginine influences the

production of the human growth hormone. The decoction prepared by boiling
the ripe fruit in water is useful for curing enduring diarrhea and dysentery
among children. Papaya plant extracts prevent ulcer in rats in a dose-
dependent manner.15
As part of evolutionary biology, plants have developed sophisticated active
defense mechanisms against infectious agents16 and mechanisms for multiple
uses of stored molecules by conversion into metabolites or recycling.
Researchers have now become more interested in phytochemicals from
edible plants about natural products of higher plants due to novel source of
antimicrobial agents.
The antimicrobial activities of methanolic solvent extract of Carica papaya leaf
were tested against the gram-positive and gram-negative bacterial strains and
fungus by observing the zone of inhibition. The antimicrobial test was
performed by disc diffusion method. The gram-positive bacteria used in the
test were Staphylococcus saprophyticus, Streptococcus pyogenes,
Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, β-hemolytic
streptococcus, Bacillus megaterium and the gram-negative bacteria were
Escherichia coli, Shigella dysenteriae, Salmonella paratyphi, Shigella boydii
and fungus like Asperllius niger and Candida albicans were also used. The
crude methanolic extract of Carica papaya leaf showed mild to moderate
antimicrobial activities against the microorganisms at different concentrations
of 50 µg/disc, 100 µg/disc and 150 µg/disc. However, no activity was found
against Streptococcus pyogenes and Shigella boydii.17
Research showed very significant broad spectrum antimicrobial activity
against Gram-negative and Gram-positive bacteria and fungi. The organic
extracts were more effective than aqueous extracts. The result further showed
that the dry sample was effective against both Gram-positive and Gram-
negative bacteria while the fresh sample was more effective against Gram-
negative bacteria. The dried leaf extract was potent against some of the
bacteria which standard antibiotics were not able to inhibit. C. papaya leaves
showed a better antibacterial activity than antifungal activity. Demonstration of
antimicrobial activity against the test isolates is an indication that there is
possibility of sourcing alternative antibiotic substances in this plant for the
development of newer antibacterial agents. Including anti-fungal agents.18
Treatment of diabetics
The aqueous extract of Carica papaya (0.75 g and 1.5 g/100 mL) significantly
decreased blood glucose levels (p<0.05) in diabetic rats. It also decreased
cholesterol, triacylglycerol and amino-transferases blood levels. Low plasma

insulin levels did not change after treatment in diabetic rats, but they
significantly increased in non-diabetic animals. Pancreatic islet cells were
normal in non-diabetic treated animals, whereas in diabetic treated rats, C.
papaya could help islet regeneration manifested as preservation of cell size.
In the liver of diabetic treated rats, C. papaya prevented hepatocyte
disruption, as well as accumulation of glycogen and lipids. Finally, an
antioxidant effect of C. papaya extract was also detected in diabetic rats. This
study showed that the aqueous extract of C. papaya exerted a hypoglycemic
and antioxidant effect; it also improved the lipid profile in diabetic rats. In
addition, the leaf extract positively affected integrity and function of both liver
and pancreas.19
Papaya leaf in modern dengue treatment
Papaya is used in Ayurveda. There is information of the use of papaya leaves
traditional Malay medicine. In recent times, there have been heated
discussions and debates on the efficacy of papaya leaves in management of
dengue fever especially in increasing platelet count in dengue patients with
low platelet count and in those who develop hemorrhagic dengue fever. The
fruit juice and leaf extract have been demonstrated to have a wide variety of
properties including anticancer, antioxidative, anti-inflammatory, anti-bacterial,
nephroprotective, hepatoprotective, hypoglycemic and hypolipidemic effects
and anti-sickling effect in sickle cell disease.
Dengue is a viral disease that today affects a vast number of people in over
125 countries and is responsible for a sizable number of deaths. In the
absence of an effective antiviral drug to treat the disease, various treatments
are being investigated. Studies have indicated that the juice of the leaves of
the Carica papaya plant from the family Caricaceae could help to increase the
platelet levels in these patients. There had been widespread reporting on the
efficacy in dengue fever, at times appearing in the media in India and
especially the state of Kerala. One of the most disturbing aspects of the
problem of dengue is that there are no effective antiviral agents available to
treat dengue complications.20 Plant derived compounds remain a significant
source for the development of new antiviral agents.
Thrombocytopenia is a common feature of the illness.21 Thrombocytopenia is
any disorder in which there is an abnormally low amount of platelets
(thrombocytes). Thrombocytopenia is common in people with cancer,
especially in those receiving chemotherapy. Deaths due to dengue are usually
a consequence of patients developing complications like dengue hemorrhagic
fever and dengue shock syndrome.22 Dengue hemorrhagic fever, if untreated,
has a mortality rate of 10-20%. It occurs due to progression of
thrombocytopenia and development of increased vascular permeability and

plasma leakage. It progresses to dengue shock syndrome, which is again
associated with high mortality.23 Platelets may also show an increased
reaction with leucocytes and endothelial cells, leading to their destruction.
Platelet dysfunction due to abnormal activation and inhibition of platelet
aggregation in dengue patients may also be responsible for the destruction.
Recent studies indicate a direct infection of the platelets by the dengue virus.
Increased levels of mediators like tumor necrosis factor-α and interleukin-1β
were associated with the thrombocytopenia.24 Edible plants with
phytochemical compliments that improve platelet count and stabilize
membranes of blood cells has thus attracted research interest.
Six serologically confirmed patients suffering from dengue received 2 doses of
papaya leaf extract at intervals of 8 hours. They also received standard
symptomatic care for dengue. The study found an increase in platelet count
and total white blood cell count in patients administered papaya leaf extract
within 24 h of treatment with the extract.25
One clinical study, which is a randomized controlled trial in 228 patients
reported significant increase in platelet production in patients with dengue and
dengue hemorrhagic fever after administration of papaya leaves. Patients in
the intervention group were administered fresh juice from 50 g of C.
papaya leaves once a day 15 min after breakfast for 3 consecutive days. In
addition, they received the standard treatment for dengue. The controls only
received the standard treatment. The final analysis was conducted on 111
patients from the intervention group and 117 controls. The study found that
there was a significant increase in the platelet counts in the intervention group
at the end of 40 h when compared to the counts 8 h after the intervention
began. This significant increase was not observed in the control group.26
Fresh papaya leaf juice tends to accelerate increase in platelet count. This is
an important factor in therapy.
The juice prepared from C. papaya leaves recorded significance increase of
platelet count in a randomized controlled trial conducted on patients with
dengue fever and dengue hemorrhagic fever. Fresh C. papaya leaf extract
significantly increased the platelet and RBC counts in the test group as
compared to controls. This study in murine model also evidenced increase in
platelet and RBC count without any acute toxicity after oral administration of
C. papaya extract. Thus, it is very important to identify those phytochemicals
of C. papaya leaves for further study as medication to boost thrombopoiesis
and erythropoiesis in humans and in animals in which these cell lineages
have been compromised27 or studied for better effects in combination with
other natural antioxidants from edible plants.

In another study, for the treatment of Dengue fever the extract was prepared
in water. 25 mL of aqueous extract of C. papaya leaves was administered to
patient infected with Dengue fever twice daily i.e. morning and evening for five
consecutive days. Before the extract administration the blood samples from
patient were analyzed. Platelets count (PLT), White Blood Cells (WBC) and
Neutrophils (NEUT) decreased from 176×10(3)/µL, 8.10×10(3)/µL, 84.0% to
55×10(3)/µL, 3.7×10(3)/µL and 46.0%. Subsequently, the blood samples were
rechecked after the administration of leaves extract. It was observed that the
PLT count increased from 55×10(3)/µL to 168×10(3)/µL, WBC from
3.7×10(3)/µL to 7.7×10(3)/µL and NEUT from 46.0% to 78.3%. This research
showed that Carica papaya leaves aqueous extract exhibited potential activity
against dengue fever. Furthermore, the different parts of this valuable specie
can be further used as a strong natural candidate against viral diseases.28
This research is of special importance because it proves that there is anti-viral
activity and consequent improvement in platelet count by using a much safer
alternative compared to drugs.
Dengue hemorrhagic disease is caused by dengue virus. The viral non-
structural 2B and 3 (NS2B-NS3) protease complex is crucial for virus
replication and hence, it is considered to be a good anti-viral target.
Researchers analyzed the anti-dengue activities of the extracts from Carica
papaya by using bioinformatics tools. They found that the flavonoid quercetin
with highest binding energy against NS2B-NS3 protease which is evident by
the formation of six hydrogen bonds with the amino acid residues at the
binding site of the receptor. The results suggest that the flavonoids
from Carica papaya have significant anti-dengue activities. The observations
suggest that the flavonoid quercetin in Carica papaya might exert its antiviral
activity by blocking the viral assembly mechanism of DENV2 virus.29
Flavonoid from Carica papaya inhibits NS2B-NS3 protease and prevents
Dengue 2 viral assembly. Quercetin has also been reported to have inhibitory
effects on several viruses.30
Carica papaya L. fruit juice and leaf extracts are known to have many
beneficial medicinal properties. Recent reports have claimed possible
beneficial effects of C. papaya L. leaf juice in treating patients with dengue
viral infections. One study to evaluate the membrane stabilization potential of
C. papaya L. leaf extracts using an in vitro hemolytic assay showed that
papaya L. leaf extracts showed a significant inhibition of hemolysis in vitro and
could have a potential therapeutic effect on disease processes causing
destabilization of biological membranes.31
An interesting case to note is a report of one serologically confirmed patient
who was brought to the emergency department with severe fever of 104 °F.
Tests revealed an abrupt decline in the patient platelets counts. The patient

has been given different broad spectrum antibiotics and anti-malarial drugs
but there were no signs of improvement and his condition became worse over
time. Vomiting could not stop. About 25 mL of leaves extract was
administrated orally, twice daily for five consecutive days. In the first blood
report it was observed that the PLT count, WBC and NEUT increased to
73×103/µL, 3.8×103/µL and 56.0%, respectively. With similar dose of extracts,
on the next day the blood report indicated that the PLT count reach
to120×103/µL while WBC and NEUT reach to 4.4×103/µL and 64.2%,
respectively. On the third day, it was observed that PLT count (137×103/µL),
WBC (5.3×103/µL) and NEUT (71.1%) increased. In the fourth blood report
(PLT: 159×103/µL, WBC: 5.9×103/µL and NEUT: 73.0%) and fifth report (PLT:
168×103/µL, WBC: 7.7×103/µL and NEUT: 78.3%) the PLT, WBC and NEUT
reach normal levels.32
The key issue in the treatment of dengue fever is to offer antiviral agents
(preferably that are non-toxic or relatively safer than drugs) in order to prevent
the progression of the infection to dengue hemorrhagic fever (DHF) that could
result in death. Various research studies show that this is possible by
intervention with papaya leaf. After 5 days of oral administration of 25 mL
aqueous extract of C. papaya leaves to the patient twice daily, the PLT count
increased from 55 × 103/μL to 168 × 103/μL, WBC from 3.7 × 103/μL to
7.7103/μL and NEUT from 46.0 to 78.3 %. Increased platelets could lead to
reduced bleeding, thus avoiding progression to the severe illness of DHF.33
The growing body of information from modern research shows that papaya
fruit and papaya leaf together provide an interesting compliment of
phytochemicals for a multi-faceted antiviral therapy mediated via blocking viral
assembly and stabilization of cell membranes of blood cells to accelerate
platelet count while stimulating the immune system as well.
Antioxidants in papaya fruit and leaf – immunostimulant effect
Damage induced to cellular constituents by oxygen-derived free radicals have
been accepted to play a crucial role in the pathogenesis of a wide range of
chronic and degenerative disorders (aging, atherosclerosis,
neurodegeneration cancer, cataract), as well as in acute clinical conditions.34
A study was conducted to evaluate the antioxidant and immunostimulant
effects of Carica papaya fruit aqueous extract (CPF, Caricaceae) against
acrylamide induced oxidative stress and improvement of immune functions
which affected by free radicals liberating acrylamide in rats. The results
revealed that acrylamide caused significant increases in MDA and decrease
of GSH level, SOD and CAT (catalase) activity due to the oxidative stress
induced by acrylamide on membrane polyunsaturated fatty acids in rat’s
stomach, liver and kidney while administration of CPF aqueous extract
significantly ameliorated the increased levels of MDA and decline of GSH,

SOD and CAT activity in the stomach, liver and kidney tissues caused by
acrylamide toxicity. Acrylamide significantly decrease immune function as it
specially reduces IgG while CPF aqueous extract significantly increased
immune functions (as seen by increases in IgG and IgM).35 The improvement
in SOD and catalase activity helps to prevent the oxidation/reduction reaction
of thiocyanate with H2O2 and, in turn, prevent the harmful effects of reduced
thiocyanate.
Studies have also reported that Carica papaya contains antioxidant
phytochemicals, such as vitamin C, betacarotene, lycopene and vitamin E all
of which act as antioxidants and consumption of these antioxidant enzymes
helps to combat oxidative stress. In a small double-blind, placebo controlled
study, a fermented extract of Carica papaya was administered to elderly
patients without major diseases, the fermented Carica papaya preparation
supplemented group showed a significant enhancement of the individual’s
antioxidant defense system.36
The fruits, leaves, seeds and latex are used medicinally. Pawpaw fruits have a
juicy taste rich in antioxidant nutrients like carotene, vitamin C, vitamin B,
flavonoids, folate, panthotenic acids and minerals such as potassium and
magnesium. The fruit is also a good source of fibre. This compliment is
reported to promote the functions of cardiovascular system and provide
protection against colon cancer.37
Many of the protective functions of immune cells depend on the fluidity of the
membranes of the cell. As the concentration of polyunsaturated fatty acids in
the membranes is increased, the potential for membrane lipid peroxidation
mediated by free radicals also is increased. Lipid peroxidation decreases
membrane fluidity, which adversely affects immune responses. Mice fed on
oxidized lipids show marked atrophy of the thymus and T-cell dysfunction.
Loss of membrane fluidity has been related directly to the decreased ability of
lymphocytes to respond to challenges to the immune system.38 C. papaya L.
leaf extracts using an in vitro hemolytic assay showed that papaya L. leaf
extracts showed a significant inhibition of hemolysis in vitro and could have a
potential therapeutic effect on disease processes associated with
destabilization of biological membranes.39 These findings are in agreement
with others that concluded that the supplementation with the antioxidants
protected immune responses in individuals exposed to certain environmental
sources of free radicals.40 Carica papaya leaf may potentially serve as a good
therapeutic agent for protection against gastric ulcer and oxidative stress. In
vivo and In vitro evaluation of the antioxidant effects of dried papaya juice in
rats showed that, the blood total antioxidant power was increased significantly
while blood lipid peroxidation levels decreased significantly.41

Researchers have been interested in the antioxidant potential of Carica
papaya (C. papaya) leaf extract and its effect on hydrogen peroxide-induced
erythrocyte damage assessed by haemolysis and lipid peroxidation.
Preliminary investigation of the extract showed that the leaf possessed
significant antioxidant and free radical scavenging abilities using in vitro
models in a concentration dependent manner (P<0.05). The extract also
reduced hydrogen peroxide induced erythrocyte haemolysis and lipid
peroxidation significantly when compared with ascorbic acid (P<0.05). The
findings show that C. papaya leaves possess significant bioactive potential
which is attributed to the phytochemicals which act in synergy. Thus, the
leaves can be exploited for pharmaceutical and nutritional purposes.42
The effects of Carica papaya leaf (CPL) aqueous extract on alcohol induced
acute gastric damage and the immediate blood oxidative stress level were
studied in rats. The results showed that gastric ulcer index was significantly
reduced in rats pretreated with CPL extract as compared with alcohol treated
controls. The in vitro studies using 2,2-Diphenyl-1-Picryl-Hydrazyl (DPPH)
assay showed strong antioxidant nature of CPL extract. Biochemical analysis
indicated that the acute alcohol induced damage is reflected in the alterations
of blood oxidative indices and CPL extract offered some protection with
reduction in plasma lipid peroxidation level and increased erythrocyte
glutathione peroxidase activity. Carica papaya leaf may potentially serve as a
good therapeutic agent for protection against gastric ulcer and oxidative
stress.43 Carpaine, present in papaya leaf may have anti-microbial activity
against helicobacter pylori.
Phytochemical analysis of C. papaya leaf extract revealed the presence of
alkaloids, glycosides, flavanoids, saponins, tannins, phenols and steroids.
Natural compounds isolated from various parts of the plant such as leaves,
fruits, stem, roots, seeds have been shown to possess excellent medicinal
value. The edible part of papaya is widely used all over the world. The leaves,
seeds and juice of papaya exhibit free radical scavenging and antioxidants
activity. Its leaf can be eaten as part of salad.44 The pharmacological activity of
leaves of Mizoram folk ethnomedicinal plant C. papaya was investigated using
standard parameters. The phenolic compounds are responsible for the total
antioxidant property of plant extracts since they are capable of scavenging
free radicals and reactive oxygen species. Phenolic compounds which are
secondary metabolites play a vital role in the antioxidant as well as
antimicrobial activity. The study reveals that it has a potential antioxidant role
which might be due to the presence of high phenolic content. These findings
favor it to be used as a primary antioxidant45 which is improved when
consumed with other fruits. The unripe fruit of papaya is used as mild laxative
and abortifacient agent and leaves are used for treatment of pyrexia,

diabetes, gonorrhea, syphilis, inflammation and as a dressing component for
wounds.46
Papaya in wound healing
Aqueous extract of C. papaya significantly enhance the wound healing that
make it an ideal dressing component for treatment of wounds. 47 Fruits and
seeds of C.papaya were evaluated for wound healing activity using wound
excision model in diabetic rats showed significant reduction in the wound area
compared to untreated diabetic control. It also showed increased granulation,
elevated hydroxyproline content and deposition of collagen in the wound
area.48
Papaya latex prepared in carbapol gel for treatment of burns demonstrated
significant increase in hydroxyproline content as well as wound contraction in
Swiss albino mice.49 Diabetic mice supplemented with fermented papaya
preparation (FPP) showed effective recruitment of monocytes and
proangiogenc response by the macrophages at the wound site resulting in
wound closure.50
Biochemistry involving cyanogenic glycosides
Many economically important food plants are cyanogenic and the cyanogenic
glycosides are mostly in the form of cyanogenic monosaccharides in which
the unstable cyanohydrin moiety is stabilized by glycosidic linkage to a single
sugar residue51 and are in the inert or non-toxic form.
There are at least 25 cyanogenic glycosides known to be found in the edible
parts of plants. Cyanogenic glycosides alone are relatively non-toxic.
However, as a result of enzymatic hydrolysis by beta-glucosidase following
maceration of plant tissues as they are eaten, or by the gut microflora,
cyanogenic glycosides are broken down to release hydrogen cyanide which is
toxic to both animals and humans. The potential toxicity of a cyanogenic plant
depends primarily on its capacity to produce hydrogen cyanide. In humans,
the clinical signs of acute cyanide intoxication include rapid respiration, drop
in blood pressure, rapid pulse, dizziness, headache, stomach pain, vomiting,
diarrhea, mental confusion, twitching and convulsions. Death due to cyanide
poisoning can occur when the cyanide level exceeds the limit an individual is
able to detoxify. The acute lethal dose of hydrogen cyanide for humans is
reported to be 0.5 to 3.5 mg per kilogram of body weight. Children are
particularly at risk because of their smaller body size52 but death due to
cyanogenic cyanide is rare.

Many plants store chemicals in the form of glycosides. Apricots, peaches,
almonds and tapioca, shorgum, cassava, flaxseeds and bamboo shoots are
some examples of such plants. Cyanogenic glycoside is found naturally in
various plants e.g. cherries, plums, almonds, peaches, apricots, apples and
cassava. The chemical is usually concentrated in the seeds, kernels or wilted
leaves. The distribution of the cyanogenic glycosides (CGs) in the plant
kingdom is relatively wide, the number of CG-containing taxa is at least 2500,
and a lot of such taxa belong to families Fabaceae, Rosaceae, Linaceae,
Compositae and others. Over 1000 plant species, representing 90 families
and 250 genera have been reported to have cyanogens. These cyanogens
are toxic only when they are enzymatically degraded (hydrolyzed) to release
hydrogen cyanide (HCN)53 in large concentrations to contribute to lethal blood
levels. Cyanogens are usually relatively higher in young plants and shoots
and dramatically reduce when approaching maturity.
In plants, these chemicals, including HCN, are bound to sugar molecules in a
very stable form and are inactive but can be activated
by enzyme hydrolysis which causes the sugar to break off, releasing the
chemical for use. Many such plant glycosides are used as medications. In
animals and humans, poisons are often bound to sugar molecules as part of
their elimination from the body. There are numerous enzymes that can form
and break glycosidic bonds. The most important cleavage enzymes are the
glycoside hydrolases. Glycoside hydrolases are found in the intestinal
tract and in saliva where they degrade complex carbohydrates such as
lactose, starch, sucrose and trehalose. In the gut they are found as
glycosylphosphatidyl anchored enzymes on endothelial cells.
Researchers studied if consumption of boiled fresh roots from sweet cassava
varieties grown in Cuba resulted in exposure to cyanogenic glycosides and
their final breakdown product – cyanide or nitrogen. When adult, nonsmoking
subjects consumed 1-4 kg cassava over 2 days, their urinary levels of the
main cyanide metabolite, thiocyanate, only increased from a mean +/- SEM of
12 +/- 2 to 22 +/- 2 mumol/l, indicating a negligible cyanide exposure. Their
mean urinary linamarin, the main cyanogenic glucoside in cassava, increased
from 2 +/- 1 to 68 +/- 16 mumol/l. In a second experiment 5 subjects
consumed one meal of 0.5 kg boiled cassava that contained 105 mumol
linamarin and 8 mumol hydrogen cyanide (HCN). Quantitative urine
collections prior to and after intake showed that 28% of linamarin was
excreted during the following 24 hours, whereas a modest increase of urinary
thiocyanate (SCN) only corresponded to the small amount of free HCN
ingested. These results indicate that the dominant cyanogen in boiled
cassava is glycosides that pass through the human body without causing
cyanide exposure.54

Thiocyanate by itself is not harmful to the immune system. Thiocyanate
shares its negative charge approximately equally between sulfur and nitrogen
atoms. However, in the presence of H2O2, it can lose that shared electron and
becomes reduced and begins to act as a free radical but the induced
reduction of H2O2 by thiocyanate is a slow reaction.55 The reduced
thiocyanate56 in the human body, (e.g., in cystic fibrosis) is damaging to the
human host defense system.57 This research together with the Cuba cassava
study shows that cyanogenic glycosides do not release HCN during
metabolism but thiocyanate is produced which is harmful only when it
undergoes oxidation/reduction and fairly large concentrations of the reduced
thiocyanate produce toxicity and hence, exposure to cassava cyanogenic
glycosides rarely produces toxicity. However, oxidation/reduction reaction
between thiocyanate and H2O2 can be prevented by sufficient amounts of
natural antioxidant intake to support sufficient levels of SOD and catalase.
Catalase is an enzyme that converts H2O2 formed by the reaction of SOD with
oxygen free radical, which are a natural byproduct of metabolism to yield
oxygen and H2O2.
Cyanogenesis describes the ability of living organisms to liberate hydrogen
cyanide from stored cyanogenic glycosides, cyanogenic lipids or cyanohydrins
on tissue damage by hydrolysis and/or decomposition. It was initially
understood as only releasing HCN, perhaps as part of a defense mechanism.
Today it is generally accepted that cyanogenic glycosides also may serve as s
storage form for reduced nitrogen and sugar. Antioxidant controlled
biochemical pathways driven by antioxidants tend to manage the release of
nitrogen which is required in young plants and shoots for rapid growth.
Humans are able to detoxify considerable amounts of HCN. Although acute
toxicity is rare, the daily consumption of sub-acute amounts of cyanogenic
glycosides leads to chronic diseases, caused by increased plasma levels of
the human detoxification products58 which indicates that salads with a small
quantity of papaya leaf with papaya fruit and other fruits would eliminate any
risk of chronic disease arising from cyanogenic glycosides.
Clearly there are two different biochemical pathways: in one, there is release
of trace amounts of hydrogen cyanide when young shoots are crushed and
the other release nitrogen from the hydrogen cyanide as a source of reduced
nitrogen for metabolism (and for making molecules and amino acids that
require nitrogen) and so while there is relatively higher amounts of cyanogenic
glycosides in young plants or shoots, it can reduce by 95% at the end of
development as in mature leaves.59 The endogenous turnover of cyanogenic
glycosides without the liberation of HCN, but nitrogen instead, may offer
plants an important source of reduced nitrogen at specific developmental
stages. The recycling of cyanogenic glycosides and the biological significance
of the presence of the turnover products in cyanogenic plants open entirely

new insights into the multiplicity of biological roles cyanogenic glycosides may
play in plants60 and this recycling in the human body may explain the
negligible cyanide exposure upon consuming the wide range of plant food that
contain cyanogenic glycosides, especially in a diet rich in natural antioxidants.
Papaya toxicity – safety profile
Sub-chronic toxicity effect of the leaf extract of Carica papaya (Linn.) in
Sprague Dawley (SD) rats was investigated. The extract was prepared by
dissolving the freeze dried extract of the leaves in distilled water and was
administered orally to SD rats (consisted of 10 rats/sex/group) at 0 (control),
0.01, 0.14, and 2?g/kg body weight (BW) for 13 weeks. General observation,
mortality, and food and water intake were monitored throughout the
experimental period. Hematological and biochemical parameters, relative
organ weights, and histopathological changes were evaluated. The study
showed that leaf extract when administered for 13 weeks did not cause any
mortality and abnormalities of behavior or changes in body weight as well as
food and water intake. There were no significant differences observed in
hematology parameters between treatment and control groups; however
significant differences were seen in biochemistry values, for example, LDH,
creatinine, total protein, and albumin. However, these changes were not
associated with histopathological changes. In conclusion, the results
suggested that daily oral administration of rats with C. papaya leaf extract for
13 weeks at a dose up to fourteen times the levels employed in traditional
medicine practice did not cause any significant toxic effect.61
While there are studies on the safety of fruits, turmeric and other plants, there
are also safety studies on papaya fruit and papaya leaf and studies on other
plants that are consumed daily which show that cyanogenic glycosides pass
through the human and animal gut without causing cyanide exposure. Studies
also show beneficial effects on platelet count without any acute toxicity after
oral administration of C. papaya extract. The papaya tree is classified as
having weak cyanogenic risk, like many other edible plants and the
concentration of cyanogenic glycoside reduces in the leaf as it approaches
maturity, as in many other plants. The standard safety tests conducted at IMR
for 28 days 90 days show no effects to the liver and kidneys. The amount of
cyanogenic glycosides in most edible plants is in trace amounts. “The lowest
dose to endanger humans is one mg per kg of body weight which means that
a 5ft 6-7inch person weighing 60 kg would require 12,000 papaya leaves at
one time to induce poisoning”62 which means that equal weight of drugs in
therapy as papaya leaf are many times more toxic than papaya or papaya
leaf. And the efficacy of papaya leaf in therapy can be improved by lowering
the trace amounts of cyanogenic compounds by mixing with papaya fruit juice

and orange. Besides, there are ways to extract that eliminate or reduce the
cyanogenic components.
Cyanogens in papaya leaf
It is estimated that there are between 50 and 100 million cases of dengue
fever (DF) and about 500 000 cases of dengue hemorrhagic fever (DHF) each
year which require hospitalization. Although dengue fever itself is rarely fatal,
it can be an extraordinarily painful and disabling illness and may become
epidemic in a population following the introduction of a new serotype. Dengue
fever is usually a self-limiting illness and only supportive care is required.
Acetaminophen may be used to treat patients with symptomatic fever. Aspirin,
brufen nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics and
corticosteroids should be avoided as these do not help but cause gastritis
and/or bleeding.63
There is concern that the metabolic break down of cyanogenic glycosides in
papaya leaf may release large amounts of hydrogen cyanide (HCN) which
may lead to toxic effects. Hydrogen cyanide is the chemical responsible for
tissue hypoxia. Chronic exposure to HCN may cause neurological, respiratory,
cardiovascular and thyroid defects. Hydrogen cyanide can inhibit the electron
transport system in the mitochondria processes of cells, inhibiting many
metalloenzymes and the cytochrome oxidase causing them to die very
quickly but the body rapidly detoxifies (trace) cyanide and an adult human
can withstand 50-60 ppm for an hour without serious consequences.
However, exposure to concentrations of 200-500 ppm for 30 minutes is
usually fatal.62 Only high concentrations are toxic and fatal and hence liver
and kidney damage must be documented to show the nature of the damage
to cells including morphological or histopathological changes, if any. Since
hydrogen cyanide kills cells rapidly, its nature of damage in the liver and
kidneys must be congruous to cell death rather than pathological changes.
Only high concentrations of HCN from eating thousands of leaves daily can
lead to organ failure and death. Hence, it has a good safety profile which
better than most drugs. The key implication of the body of scientific
information shows that the safety profile makes papaya and papaya leaf an
attractive element in the pharmaceutical/nutraceutical and cosmetics industry
in view of its phytochemicals, antimicrobial activity, antioxidants, anti-
inflammatory and immunostimulant properties and membrane stabilization
properties.
Conclusion
The various reports published in scientific literature show that C. papaya L.
leaf extract does have beneficial properties in dengue. It has been shown to

bring about a rapid increase in platelet count and it has membrane-stabilizing
property. C. papaya is a multi-faceted plant due to its compliment comprising
a range of antioxidants and phytochemicals many of which are converted into
secondary metabolites that are beneficial for health and therapy. It is
imperative to identify the mechanism of its phytochemicals that act in synergy
with its antioxidants to improve its efficacy in therapy. It is a rich source of
vitamins, antioxidants, flavanoids, polyphenols, etc. and regular intake of
papaya improves health by quenching the free radicals generated in the body
and improves immune function. More and more compounds are being isolated
from the C. papaya and studied in clinical nutrition and for therapeutic use and
the number of clinical studies are increasing because of the huge potential to
find active compounds and principles of synergy with other edible herbs for
the growing market that actively seeks effective and natural solutions that are
safer than drugs which could be beneficial for mankind in targeting various
diseases and for use in cosmetics and for anti-aging effects, which is growing
rapidly due to advances in telomeric length, membrane stabilization, DNA
repair proteins etc., and for the biologics sector. It is an important plant in an
industry that began to grow about 30 years ago with better understanding of
phytochemicals and their conversion into secondary metabolites and natural
antioxidants that support the body’s natural healing process and their role in
biochemical pathways that yield bio-molecules in the body. Isolation of papaya
quercetin may be very useful in biologics. Due to the wide scope and potential
of developing safer therapeutic interventions from edible plants and herbs and
fruits, third world governments or developing state that intend to do so must
anticipate such attacks on their results and programs and doubtful stories
dished out to the media for dissemination to the public that attack natural
remedies must be investigated by a panel of experts.
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Declaration: This research was not supported or funded by any grants or institution
or corporate body. IP/copyright;beldeusingh.