Received: 20 Sep 2019, Revised and Accepted: 25 Dec 2019
The review outlines the current understandings of saponins and sapogenins in agave species with special focus on pharmacological role of hecogenin in
numerous preclinical studies. A systematic literature survey was done on the pharmacological activities of hecogenin during the past 40 y with
electronic databases like PubMed, Science Direct, Wiley, SciFinder, Google Scholar, Web of Science and Scopus. Hecogenin, a steroidal sapogenin found
abundantly in the leaves of Agave genus species such as, Agave sisalana, Agave cantala, Agave aurea and many more. This phytosteroid (hecogenin) is
used as initial material for the synthesis of steroidal drugs in the pharmaceutical industry. Hecogenin has exhibited potential role in the management of
a number of disorders such as inflammation, arthritis, cancer, gastric ulcer, cardiotonic and larvicidal activity. In this review, we have summarized the
saponins and sapogenins present in the Agave species and pharmacological roles of hecogenin with their mechanism of action.
SAPONINS AND SAPOGENINS OF AGAVE WITH RESPECT TO DIVERSE PHARMACOLOGICAL
ROLE OF HECOGENIN
DEEPA K. INGAWALE (MANDLIK)
Bharati Vidyapeeth University (Deemed to be University), Poona College of Pharmacy, Erandawane, Pune 411038, Maharashtra, India
Keywords: Agave genus, Saponin, Sapogenin, Hecogenin, Pharmacological activities
© 2020 The Authors. Published by I nnovare Academic Sciences Pvt Ltd. This i s an open access article under the CC BY license (http://creativecommons.org /licens es/by/4.0 /)
DOI: http://dx.do i.org/10.22159/ijpps.2020v12 i2.35789. Journal homepage: htt ps://innovareacademics.in/journals/index.php/ijpps
The genus Agave contains above 400 species growing in dry and
semi-dry environments belongs to the family Agavaceae (fig. 1).
These plants are often called as ‘wild century’, ‘hardy century,’ or
‘rough century’ plants as they are growing in dry lands. The plant is
also known as ‘century plant’ indicates a huge application of Agave
plant . Beverages, fiber and food materials have been obtained
from the agave plants . In the recent times, Agave species have
also been used as a nutraceutical, natural sweeteners, prebiotics,
biofuels and source of steroidal sapogenins . The research work
on Agave saponins was initially presented by Jones et al. in 1932 .
Moreover, Agave was considered as a novel and budding source of
sapogenins . Up till now, not less than 50 species of Agave plants
have been discovered for their sapogenin and saponin
phytoconstituents. The previous review work has furnished a
phytochemistry summary of the family belonging to Agavaceae .
It comprised of several saponins and sapogenins of Agave such as
Dracaena, Yucca, Cordyline, Nolina, Furcraea and Sansevieria. The
other review entitled traditional products of Agave species has
presented information about Agave food, nutraceutical and
pharmacological properties of extracts .
Fig. 1: Different species of Agave genus
International Journal of Pharmacy and Pharmaceutical Sciences
Print ISSN: 2656-0097 | Online ISSN: 0975-1491 Vol 12, Issue 2, 2020
Int J Pharm Pharm Sci, Vol 12, Issue 2, 1-7
Saponins are the glycosides of steroids or triterpenes with numeral
of pharmacological activities like anti-oxidant, immuno-stimulant,
anti-inflammatory, anti-cancer, adjuvant, anti-microbial, hypo-
cholesterolemic properties . In current days, biologists and
chemists are focusing their attention on saponins for the purpose of
new drug discovery [9, 10]. The applicability of these steroidal
compounds has been increasing for therapeutic purpose along with
principal component in the drug discovery methodologies .
Over the years, the interest of many researchers has been increasing
due to industrial applicability of steroidal sapogenins. In addition to
this, hecogenin exhibits variety of important biological activities in
the pharmaceutical industry [12, 13]. The steroidal sapogenins
(hecogenin) from Agave genus were reported to have a number of
pharmacological activities such as anti-inflammatory, analgesic, anti-
arthritis, gastroprotective, anticancer and larvicidal activity [14-18].
Overall, the results of numerous pharmacological studies have been
linking the possible use of hecogenin as a novel multi-target based
therapeutic agent against abundant long-lasting disease conditions.
The present review emphasizes on steroidal saponins and
sapogenins of Agave genus with numerous pharmacological
activities with respect to their mechanism of action.
Saponins and sapogenins from agave genus
Different Agave species has been reported for various primary and
secondary metabolites. Carbohydrates , Agave syrups as a
functional foods, natural sweeteners, prebiotics  are the examples
of primary metabolites from Agave whereas, the examples of
secondary metabolites includes sterols, steroidal saponins and
sapogenins , flavonoids , homoisoflavonoids , tannins
, phenolic acids , volatile coumarins , long chain alkanes,
fatty acids and alcohols [21, 23]. Steroidal saponins and sapogenins
are the most commonly studied compounds in Agave genus.
Two different steroidal sapogenins are identified from the Agave such
as spirostanol-type (1-27) and cholestane-type (Agavegenin D-28). Up
till now, sapogenins of furostanol and furospirostanol skeleton have
not been discovered in Agave genus. 16, 22; 22, 26-
bisepoxycholestanes gives rise to spirostanols sapogenins. The
spirostanol skeleton made up of a tetrahydrofuran ring and a
tetrahydropyran ring attached to C-22 position in a spiran fashion.
Spirostanols sapogenins are isolated from the callus cultures, flowers,
leaves, leaf juice, rhizomes of Agave plants. Spirostanol sapogenins of
Agave differ from each other in terms of a) presence or absence of
carbonyl group at C-12, b) configuration and number of the hydroxyl
moieties attached to the parent nucleus, c) presence or absence of
unsaturation in rings B or C and d) configuration of H at C-5 and C-25.
A hydrophobic aglycone (sapogenin) unit and a hydrophilic sugar
(glycone) unit combines together to form a saponin molecule. The
sugar moieties of Agave saponins include β-D-glucopyranosyl, β-D-
xylopyranosyl, β-D-galactopyranosyl and α-L-rhamnopyranosyls.
The saponins of Agave are classified into two types such as
spirostanol and furostanol glycosides, depending on the basis of
sapogenin nucleus present in it. These compounds are further
classified into monoglycosides, diglycosides, triglycosides,
tetraglycosides, pentaglycosides or hexaglycosides on the basis of
number of sugars moieties attached to it. If the sugar chain is
present at only one position of the sapogenin, it is called as
monodesmosidic. Bidesmosidic saponins contains, two sugar units
located at two different points of sapogenin . The spirostanol
saponins of Agave are monodesmosidic and have sugar unit attached
at the C-3 position of aglycone moiety. Bidesmosidic spirostanol
saponins are relatively very rare in Agave plants.
Reported pharmacological roles of hecogenin
Hecogenin is a steroidal sapogenin (fig. 2) isolated from the leaves of
Agave genus species such as Agave cantala, Agave sisalana, Agave
aurea and many more . The cultivation of hecogenin is extensively
spread throughout the tropical and subtropical regions . Brazil
represents one of the largest producers (69 %) of hecogenin .
Hecogenin was reported as an important therapeutic agent due to its
valuable pharmacological properties involving antioxidant, anti-
inflammatory, antifungal, hypotensive, anti-nociceptive , larvicidal,
cardioactive, anti-proliferative activity in human osteosarcoma cells
 and anti-hyperalgesic effects . Hecogenin also exhibits an anti-
inflammatory effect against gastric mucosal inflammation in rat
induced by ethanol . It is also used in pharmaceutical industry as a
precursor for the synthesis of many steroidal hormone and steroidal
anti-inflammatory drugs [32
Fig. 2: Structure of hecogenin
Anti-inflammatory role of hecogenin
Inflammation is a multidimensional reaction of body tissues to
harmful stimuli. It is a protective mechanism involving the activities
of immune cells, molecular signals and vascular events. During the
inflammation process, a wide range of inflammatory cytokines,
chemical mediators and oxygen-derived free radicals are generated
from the inflammatory and phagocytic cells that causes onset of
inflammation reaction . The treatment of inflammatory diseases
involves the usage of non-steroid anti-inflammatory drugs (NSAID’s)
and other synthetic medications. The NSAID’s and synthetic anti-
inflammatory drugs provide symptomatic relief and have numerous
side effects. These drugs do not change the mechanism of
inflammation, increases drug resistance and display inadequate
target specificity. Hence, to overcome all these problems associated
with synthetic anti-inflammatory drugs, it is needed to search a drug
from natural source without or minimal side effects . Ingawale
and Patel, (2016) have explored the anti-inflammatory effect of
hecogenin against croton oil induced ear edema in mice and cotton
pellet induced granuloma in rat model. Result showed that,
hecogenin significantly decreases the weight of inflamed ear of
croton oil treated mice and percent inhibition of dry weight of
granuloma tissue in cotton pellet induced granuloma model in rat
was also found to be significantly decreased. Further, it also
suppressed the myeloperoxidase and serum levels of Tumour
necrosis factor-α (TNF-α) and Interleukin-6 (IL-6) in cotton pellets
induced granuloma model in rat. The result was further supported
by histopathological analysis of ear tissue that showed significant
decrease in dermal thickness and epidermal hyperplasia of ear
tissue thus confirming its anti-inflammatory activity  (fig. 3).
Nociceptive role of hecogenin
The pain sensation plays an imperative role as a protection and an
alerting mechanism against the tissue damage. The endogenous pain
inhibitory systems alter the pain sensations through the descending
pain pathway system and release of neurotransmitter such as
serotonin, noradrenalin, and endogenous opioids. The severity of pain
sensation is reduced by the activation of descending pain pathway that
lessens the transmission of nociceptive information . Gama et al.,
(2013) have studied the anti-noceiceptive effect of hecogenin in tail
flick and rota rod test in mice. In this study, the nociceptive threshold
was evaluated by tail flick test and motor performance by rota rod test
in mice. The intraperitoneal (i. p.) administration of hecogenin acetate
(5−40 mg/kg) increased the tail flick latency time in a dose-dependent
manner whereas; the systemic administration of hecogenin acetate
Int J Pharm Pharm Sci, Vol 12, Issue 2, 1-7
(5−40 mg/kg) increased the Fos positive cells concentration in the
gray mater. The data was further supported by immuno-histochemical
detection of Fos protein expression in the gray mater. In addition to
that, hecogenin acetate has promoted neuronal activation in the gray
mater (main site of descending pain-inhibitory pathways) . These
data have confirmed that hecogenin acetate produces anti-nociceptive
effect through the activation of opioid receptors and by endogenous
analgesic mechanisms . The anti-hyperalgesic activity of hecogenin
acetate was tested in inflammatory models of mice with measurement
of cytokine levels and c-fos expression on spinal cord area. The pre-
treatment of mice with hecogenin acetate (5, 10, or 20 mg/kg; i. p.)
inhibited the progress of mechanical hyperalgesia induced by TNF-α,
carrageenan, dopamine and prostaglandins E2
Fig. 3: Anti-inflammatory role of Hecogenin
. Furthermore, the
immunofluorescence data confirmed that pre-treatment of mice with
hecogenin acetate, significantly inhibited Fos expressions in the dorsal
horn of spinal cord after carrageenan induced inflammation. The
present results suggest that hecogenin acetate attenuates mechanical
hyperalgesia by blocking c-fos expression in the spinal cord and by
reduction of pro-inflammatory cytokines, such as interleukin-1β (IL-
1β)  (fig. 4).
Fig. 4: Nociceptive role of Hecogenin
Larvicidal role of hecogenin
Dengue is a viral disease caused by the dengue virus, belonging to
the family Flaviviridae. Dengue is communicated by several
mosquito species of the genus Aedes, mainly Aedes aegypti. The
control of dengue is depends on the mosquito combat, through the
use of chemical insecticides. Oliveira et al., (2014), have examined
the larvicidal activity of hecogenin acetate against Aedes aegypti
Int J Pharm Pharm Sci, Vol 12, Issue 2, 1-7
larvae. Experimental result indicated that the hecogenin acetate
does not killed larvaes in the first 24 and 48 h, killed 10% of larvaes
after 72 h, 80% of larvaes after 96 h and 95% of larvaes in 120 h in
the concentration. The probable mechanism of larvicidal activity of
hecogenin acetate was mimicking the insect growth hormone,
preventing its development and death of virus  (fig. 5).
Fig. 5: Larvicidal role of hecogenin
Gastroprotective role of hecogenin
Gastric ulcer is a lesion on the mucosal epithelium of the stomach on
exposure to excessive acid and destructive pepsin . Gastric
ulceration is the very common gastrointestinal disorder, accounting
for 15 mortality cases out of every 15,000 complications in the world
per year . The treatment of gastric ulcer involves the usage of
various techniques and medications such as vagotomy, prostaglandin
The gastroprotective activity of hecogenin was studied in ethanol
and indomethacin induced gastric ulcer in mice. Hecogenin pre-
treatment in rats significantly reduced the gastric lesion in ethanol
and indomethacin induced gastric ulcer in rats. The levels of lipid
peroxidation and nitrite were found to be decreased with increased
cyclooxygenase-2 (COX-2) expression. The gastroprotective effect of
hecogenin was exhibited due to the synthesis of prostaglandin,
opening of K
receptor antagonists and antacids to proton pump
inhibitors. But, the above treatment is associated with gastrointestinal
toxicity specifically due to NSAID’s . Currently available synthetic
antiulcer drugs like ranitidine, cimetidine, misoprostol, omeprazole
and esomeprazole are used for the management and treatment of
NSAID induced gastric ulcer. But, these drugs are associated with
simpler to severe side effects, provoking a search for non-toxic,
affordable and easy availability of antiulcer medication [40, 41].
Exploration on the phytosteroids of medicinal plants that are widely
used in the traditional systems of medicine might provide efficient
remedy for the gastric ulcer treatment.
ATP channels and decreasing release of
myeloperoxidase from neutrophils in vitro. These gastroprotective
effects were confirmed by histological data of hecogenin in ethanol
induced gastric ulcer in rats. The probable mechanism behind the
gastroprotective activity would be antioxidant properties,
generation of free radicals by increasing the glutathione level and
the blockade of lipoperoxidation  (fig. 6).
Fig. 6: Gastroprotective role of hecogenin
Int J Pharm Pharm Sci, Vol 12, Issue 2, 1-7
Anti-rheumatic role of hecogenin
Rheumatoid arthritis is a systemic and chronic autoimmune joint
disorder characterized by inflammation of the synovial membrane,
hyperplasia, cartilage and functional disability of joints due to
imbalance between pro-inflammatory and anti-inflammatory
cytokines lead to auto-immunity sensitization and chronic
inflammation [42, 43]. Inflammatory mediators play an imperious
role in the joint inflammation and damage process during the
development of rheumatoid arthritis . The drug treatment of
rheumatoid arthritis have been transformed from conventional non-
steroidal anti-inflammatory drugs including aceclofenac, ibuprofen
and naproxen with prednisone hormones and or disease-modifying
anti-rheumatic drugs such as sulfasalazine, methotrexate and
leflunomide to novel biological agents such as decoy TNF-α receptor
and TNF-α antibody . But, these treatments are allied to several
side effects such as hematologic toxicity, gastrointestinal
nephropathy, ulcerogenicity, cardiovascular complication and
therefore, increase the cost of therapy . Therefore, it is utmost
emergency to develop a safer, new, efficient and economical agent
for the treatment of rheumatoid arthritis.
Liagre et al., (2007) reported the anti-inflammatory effects of
hecogenin in rheumatoid arthritis synovial cell survival. The results
of study have shown that hecogenin inhibited the proliferation and
induced apoptosis of human rheumatoid arthritis. The apoptosis
induced by hecogenin was associated with overexpression of COX-2
enzyme activity correlated with the overproduction of endogenous
prostaglandins E2, activation of mitogen activated protein kinase,
DNA fragmentation, activation of caspase-3 and 9 a major markers of
apoptosis . Ingawale and Patel, 2018 have reported the anti-
arthritic activity of hecogenin through the suppression of pro-
inflammatory cytokines in complete freund’s adjuvant induced
arthritis in rats. Results of the study have shown that hecogenin
elicited significant reduction in the paw edema, arthritic score and
joint diameter along with inhibition of joint destruction in
histopathological and radiological analyzes of ankle joint. The
biochemical level of serum transaminase serum phosphatase,
myeloperoxidase level, haematological parameters such as
haemoglobin, blood cells and inflammatory cytokines levels such as
TNF-α, IL-6, Interleukin-12 (IL-12) and Thromboxane B2 (TXB 2
Fig. 7: Anti-rheumatic role of hecogenin
were found to be decreased after the treatment of hecogenin. The
anti-arthiritc effect was supported by histopathological and COX-2
mRNA expression of rats. In histopathological analysis, the ankle
joint treated with hecogenin showed pronounced inhibition of joint
space narrowing, soft tissue swelling and bone erosion of ankle joint.
The COX-2 expression of the hecogenin treated rats exhibited
reduced levels of COX-2 mRNA enzymes indicating the anti-arthiritc
activity of hecogenin  (fig. 7).
Fig. 8: Anti-cancerous role of hecogenin
Int J Pharm Pharm Sci, Vol 12, Issue 2, 1-7
Anti-cancer role of hecogenin
Cancer is one of the world’s most health concern and act as a
primary medicinal chemistry and pharmacology targets. Breast
cancer is the most common malignancy condition affecting the
females worldwide. Breast cancer accounts for 25% of all the cancer
cases and 15% of cancerous deaths among females .
Furthermore, breast cancer is considered as the leading cause of
disability due to the deficiency of early diagnosis and effective
treatments. Chemotherapy is the reputable forefront treatment for
the treatment of cancer, but selectivity and off-target side effects are
leading concerns. The treatment from cytotoxic chemotherapy has
been surprising changed to successful molecular targeted cancer
therapy, with significant safety .
Elsayed et al., (2017) have studied the anticancer effect of hecogenin
thiosemicarbazone analogs as novel mitogen activated protein
kinase/extracellular signal-regulated kinase (MEK) inhibitors for the
control of breast cancer. In this study they have prepared thirty three
analogs and tested on various in vitro (cell proliferation, cytotoxicity
assay, lactate dehydrogenase release assay, migration assay, invasion
assay, protein extraction and immunoblotting assay) and in vivo model
(orthotopic xenograft model by using MDA-MB-231/GFP human breast
cancer cells), among which hecogenin 12-(30-methylphenyl
thiosemicarbazone) have demonstrated the most potent anti-
proliferative, anti-migratory and anti-invasive activities at low
concentration level . Cruz et al., (2016) have reported that cytotoxic,
genotoxic and mutagenic effects of hecogenin on HepG2 cells. Hecogenin
cytotoxicity was studied by performing MTT assay. Genotoxic and
mutagenic potentials of hecogenin were assessed by comet assay and
cytokinesis-block micronucleus assay. The result revealed that cell
treated with hecogenin, no cytotoxic effect was observed on HepG2 cells
in 10 μm and 50 μm concentrations range. Furthermore, exposure of
cells to 100 μm of hecogenin demonstrated a slight reduction in cell
viability, whereas treatments with concentration above than 100 μm, cell
viability decreased significantly by 30%  (fig. 8).
The current review article emphasized on the phytochemistry of
saponins and sapogenins especially hecogenin isolated from Agave
plants and their pharmacological roles. Hecogenin (steroidal saponin)
found in a number of agave species is reported to have variety of
multidimensional biological and therapeutic effects including anti-
inflammatory, anti-cancer, anti-rheumatic, gastroprotective, larvicidal,
nociceptive activities. Because of this reason, hecogenin is a main
biomolecule of interests in the prevention or treatment of numerous
illnesses. The protective effects of hecogenin are due to multiple
mechanisms including suppression of myeloperoxidase levels and
serum levels of TNF-α and IL-6 in inflammation model, anti-
nociceptive effect through the activation of opioid receptors and
blocking c-FOS expression in the spinal cord and reducing the level of
pro-inflammatory cytokines such as IL-1β, gastroprotective effect due
to antioxidant properties, generation of free radicals by increasing the
glutathione level and the blockade of lipid peroxidation, anti-arthritic
effect due to reduced levels of COX-2 mRNA enzymes and serum pro-
inflammatory cytokines such as TNF-α, IL-6, IL-12 and TXB2
these collected information we can conclude that hecogenin has
various exciting pharmacological potential such as anti-inflammatory,
anti-nociceptive, antimicrobial, gastroprotective, anti-rheumatic,
anticancer and larvicidal aspects.
The authors want to acknowledge Poona college of Pharmacy, Pune
for online article support.
All the have been carried out by me.
CONFLICTS OF INTERESTS
The author has no conflicts of interest to declare.
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