Occurrence, isolation and characteristic features (Chemical nature, uses in pharmacy, medicinal and health benefits) of Naringin

1. Naringin
Kaustav Dey
M. Pharm (Pharmacognosy) 1st Sem
University Institute of Pharmaceutical Sciences
Panjab University

2. Contents
 Introduction
 Sources
 Extraction & Isolation
 Chemistry & its properties
 Toxicity
 Medicinal benefits & Uses

3. Introduction
 Naringin is an flavanone glycoside present in citrus fruits with
interesting biological and pharmacological actions.
 Naringin was first discovered by De Vry in the flowers of grapefruit
trees growing in Java in 1857, but he did not publish his findings at that
time.
 Extensive research on this “novel compound” was conducted in the years
to come by De Vry and Hoffman, and, subsequently, by Will.
 It is one of the main active components of Chinese herbal medicines,
such as Drynaria fortunei (Family- Polypodiaceae), Citrus aurantium L. &
Citrus medica L. (Family- Rutaceae)

4. Introduction
 The name naringin is probably derived
from the Sanskrit term “narangi”
meaning “orange”.
 Naringin is composed of naringenin,
an aglycone and neohesperidose
attached to the hydroxyl group at C-7
and tastes bitter due to its glycosidic
moiety.
 It is abundantly contained in the skin of
grapefruit and orange and is the origin
of their bitterness.

5. Introduction
 Its aglycon is naringenin, which is synthesized by a shikimic
acid pathway and occurs naturally in citrus fruits.
 It displays strong anti-inflammatory & antioxidant activities.
 Naringenin is known to exhibit a variety of biological effects such
as enzyme inhibitors, antioxidants, and anticancer while also being
known as an anti-inflammatory agent.
 Recommended dose of naringin – 40-80 mg

6. Sources
 Naringenin and its glycoside has been found in a variety of herbs and fruits, including
○ Grapefruit
○ Bergamot
○ sour orange
○ tart cherries
○ Tomatoes
○ Cocoa
○ Greek oregano
○ water mint
○ Beans

7. Sources
 Grapefruit juice (Citrus × paradisi) (Family - Rutaceae) can provide much
higher plasma concentrations of naringenin than orange juice.
 Naringenin can be absorbed from cooked tomato paste
 It is also present in other plants including Citrus sinensis, Citrus unshiu, Citrus
nobilis Citrus tachibana, Citrus junos, (Family - Rutaceae) Artemisia
selengensis, Artemisia stolonifera, (Family - Asteraceae) roots of Cudrania
cochinchinensis (Family - Moraceae), aerial parts of Thymus herba-
barona(Family - Thymaceae), fruits of Pon cirus (Family - Rutaceae) and
related citrus species.

8. Extraction & Isolation
 Three steps are needed to isolate naringin from fruits:
extraction » separation » purification.
 The naringin content in fruit depends on a number of factors
 the time of fruit collection,
 the part of the fruit used and
 if the peel is the source of naringin, the drying time
 The naringin content of different fruits varies as follows:
Citrus aurantium (CA) > Immature CA, Immature Ponciri
fructus > Citri unshiu peel > Immature Citri unshiu peel
BITTER ORANGE (CITRUS
AURANTIUM)

9. Extraction & Isolation
A convection oven is
used to dry the peel
more quickly than sun
drying and to reduce
the aerial exposure
time and to prevent
microbial activity,
which could lead to
the destruction of
naringin and to the
contamination with
metabolites.
Extract Citrus
aurantium (CA) powder
(0.5 g) with 50%
methanol (25 mL) for
30 min using
ultrasonication,
which can help to
retard or eliminate
microbial infection.
The CA extract
achieved a 25.8%
naringin yield, and
then redissolve in
methanol to provide a
crude drug solution
with a final
concentration of
0.1 g/mL.

10. Extraction & Isolation
Methanol extraction
is followed by
crystallization with
water at 25 °C, with
the addition of 14–
15% (v/v)
dichloromethane,
and can result in a
five fold higher yield
than conventional
hot water extraction.
In this manner, ∼
20 g of naringin
(> 98% purity) can be
obtained from 1 kg
of dry pomelo peel.
After concentrating,
the structure of
naringin is confirmed
using ultraviolet-
visible spectroscopy
(UV-VIS), Fourier
transform-infrared
spectroscopy
(FTIR), 1H NMR
spectroscopy, mass
spectrometry and
elemental analysis

11. Chemistry
 Also known as naringenin-
7-rhamnoglucoside.
 Molecular formula:
C27H32O14
 Naringin is a disaccharide
derivative that is (S)-
naringenin substituted by a
2-O-(alpha-L-
rhamnopyranosyl)-beta-D-
glucopyranosyl moiety at
position 7 via a glycosidic
linkage

12. Chemistry & Properties
 IUPAC Name - (2S)-7-[4,5-dihydroxy-6-(hydroxymethyl)-3-[3,4,5-
trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-
hydroxyphenyl)-2,3-dihydrochromen-4-one
 Chemical name - 4',5,7-trihydroxyflavanone 7-rhamnoglucoside
 Molecular Weight - 580.5 Dalton
 Physical description – Solid
 Melting point - 83º C
 Solubility - 1 mg/mL at 40 °C in water
 Highly soluble in organic solvents like , ethanol, methanol & DMSO
 Sparingly soluble in aqueous buffer
 Storage – Should be stored at -20° C (Stable for 2 years)

13. Toxicity
 The typical concentration of naringin in grapefruit juice is around
400 mg/l.
 The reported LD50 of naringin in rodents in 2000 mg/kg.
 Naringin inhibits some drug-metabolizing cytochrome P450 enzymes,
including CYP3A4 and CYP1A2, which may result in drug-drug
interactions.
 Ingestion of naringin and related flavonoids can also affect the
intestinal absorption of certain drugs, leading to either an increase or
decrease in circulating drug levels.
 To avoid interference with drug absorption and metabolism, the
consumption of citrus (especially grapefruit) and other juices with
medications is advised against.

14. Medicinal Benefits & Uses

15.  Various disorders in which naringin has been documented
to be effective.
System Disorders
Chemical/radiation-
induced damage
Radioprotection
Hepatotoxicity
Nephrotoxicity
Pulmonary system Cough and bronchitis
Cardiovascular
Atherosclerosis and other thrombotic
disorders
Hypertension
Drug-induced cardiotoxicity
Myocardial infarction
Metabolic
Type 2 diabetes
Metabolic syndrome
Obesity
Diabetes neuropathy
Hyperlipidemia, insulin resistance, and
hepatic steatosis

16.  Various disorders in which naringin has been documented
to be effective.
System Disorders
Neurological
Epilepsy
Parkinsonʼs disease
Alzheimerʼs disease
Memory enhancing
Stroke
Spinal cord injury
Cognitive dysfunction
Huntingtonʼs disease
Depression
Anxiety
Cancers
Breast cancer
Colon cancer
Cancer cervix
Bladder cancer
Lung cancer
Liver cancer
Oral cavity cancers
Skin cancer

17.  Various disorders in which naringin has been documented
to be effective.
System Disorders
Bone diseases
Osteoporosis
Rheumatoid arthritis
Dental diseases Dental caries
Infections
Salmonellosis
Filariasis
Dengue
Ocular diseases
Uveitis
Cataract
Miscellaneous
Ulcerative colitis
Contact dermatitis
Allergic rhinitis
Gastric ulcer

18. Effects on bone regeneration
 Treatment with naringin for 10–30 days can enhance the bone
regeneration, BMD and bone strength in animal models, but the
effects of the dose and route of administration, as well as the
mechanism of action and side effects, remain unclear.
 Naringin has been shown to significantly affect osteogenic
differentiation and cell proliferation by improving signalling pathway
activity.
 The effect of naringin on UMR-106 and MG-63 osteosarcoma cells is
dose-dependent over the concentration range of 1–100 μg/mL

19. Anti-inflammatory effects
 Naringin has been shown to be effective in reducing the expression of
signalling factors associated with the inflammatory response, e.g.,
interleukin-6 (IL-6), interleukin-8 (IL-8), inducible nitric oxide
synthase (iNOS), nuclear factor erythroid 2-related factor 2 (Nrf2)
and TNF-α, in animal models of inflammation.
 In the 20-month-old male Wistar rats, treatment with naringin
potentially stopped an improvement in serum IL-6 during aging-
related inflammation
 In addition, naringin inhibited iNOS expression and NO production in
macrophages

20. Anti-cancer effects
 Naringin has been shown to inhibit cell proliferation and to promote
cell apoptosis in tumour cells, including triple-negative breast cancer
(TNBC) cells, human cervical cancer (SiHa) cells and bladder cancer cells.
 In TNBC cells, the pro-apoptotic activity of naringin results from G1-phase
cell cycle arrest. Suppression of the growth of breast cancer cells by
naringin is mediated by inhibition of the β-catenin pathway, leading to a
significantly increased p21 level and decreased cell survival.
 Naringin acts by a similar mechanism in SiHa cells, which exhibit apoptotic
cell death, internucleosomal DNA fragmentation, morphological changes
and a decline in the mitochondrial transmembrane potential through both
death-receptor and mitochondrial pathways.

21. Effect on oxidative stress
 Phenolic phytochemicals are thought to promote health partly via
antioxidant activity and free radical scavenging effects.
 Disturbances in the normal redox state of cells can lead to toxicity
through the production of ROS and free radicals, which damage all of
the components of the cell.
 Naringin has been shown to have dose-dependent radical scavenging
activity against 1,1-diphenyl-2-picryl-hydrazyl and
tetraethylammonium chloride radicals.
 At concentrations of 5–2000 μM, naringin showed antioxidant activity
and reduced the frequency of DNA damage by H2O2 in Chinese
hamster fibroblast cells.

22. Effect on metabolic syndrome
 Metabolic syndrome (MetS), which consists of cluster of conditions,
hypertension, hyperlipidemia, hyperglycemia, and visceral
obesity, is affecting population worldwide.
 Studies have shown that naringin plays a critical role in the treatment
of MetS due to its antioxidant activity and ability to regulate
cytokines.
 It appears to be efficacious in alleviating MetS by preventing
oxidative damage and proinflammatory cytokine release.

23. References
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https://doi.org/10.5958/0974-360X.2020.00447.3
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