Naringenin is a flavorless, colorless

flavanone The flavanones, a type of flavonoids, are various aromatic, colorless ketones derived from flavone that often occur in plants as glycosides. List of flavanones * Blumeatin * Butin * Eriodictyol * Hesperetin * Hesperidin * Homoeriodictyol * ...

, a type of flavonoid. It is the predominant flavanone in grapefruit, and is found in a variety of fruits and herbs.

Structure

Naringenin has the skeleton structure of a flavanone with three

hydroxy group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

s at the 4', 5, and 7 carbons. It may be found both in the aglycol form, naringenin, or in its

glycosidic A glycosidic bond or glycosidic linkage is a type of covalent bond that joins a carbohydrate (sugar) molecule to another group, which may or may not be another carbohydrate. A glycosidic bond is formed between the hemiacetal or hemiketal group ...

form,

naringin Naringin is a flavanone-7-''O''- glycoside between the flavanone naringenin and the disaccharide neohesperidose. The flavonoid naringin occurs naturally in citrus fruits, especially in grapefruit, where naringin is responsible for the fruit' ...

, which has the addition of the

disaccharide A disaccharide (also called a double sugar or ''biose'') is the sugar formed when two monosaccharides are joined by glycosidic linkage. Like monosaccharides, disaccharides are simple sugars soluble in water. Three common examples are sucrose, la ...

neohesperidose Neohesperidose is the disaccharide which is present in some flavonoids. It can be found in species of '' Typha.'' ''Delphinidin-3-neohesperidoside and cyanidin-3- neohesperidoside from receptacles of Podocarpus species, Oyvind M. Andersen, Phytoc ...

attached via a

linkage at carbon 7. Like the majority of flavanones, naringenin has a single chiral center at carbon 2, although the optical purity is variable.

Racemization In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic (optically inactive) form. This creates a 1:1 molar ratio of enantiomers and is referred too as a racemic mixture (i.e. conta ...

of S(-)-naringenin has been shown to occur fairly quickly.

Sources and bioavailability

Naringenin and its glycoside has been found in a variety of herbs and

fruit In botany, a fruit is the seed-bearing structure in flowering plants that is formed from the ovary after flowering. Fruits are the means by which flowering plants (also known as angiosperms) disseminate their seeds. Edible fruits in particu ...

s, including grapefruit, bergamot,

sour orange Bitter orange, Seville orange, bigarade orange, or marmalade orange is the citrus tree ''Citrus'' × ''aurantium'' and its fruit. It is native to Southeast Asia and has been spread by humans to many parts of the world. It is probably a cross bet ...

, tart cherries,

tomato The tomato is the edible berry of the plant ''Solanum lycopersicum'', commonly known as the tomato plant. The species originated in western South America, Mexico, and Central America. The Mexican Nahuatl word gave rise to the Spanish word ...

es,

cocoa Cocoa may refer to: Chocolate * Chocolate * ''Theobroma cacao'', the cocoa tree * Cocoa bean, seed of ''Theobroma cacao'' * Chocolate liquor, or cocoa liquor, pure, liquid chocolate extracted from the cocoa bean, including both cocoa butter and ...

, Greek oregano,

water mint ''Mentha aquatica'' (water mint; syn. ''Mentha hirsuta'' Huds.Euro+Med Plantbase Project''Mentha aquatica'') is a perennial flowering plant in the mint family Lamiaceae. It grows in moist places and is native to much of Europe, northwest Africa ...

, as well as in

bean A bean is the seed of several plants in the family Fabaceae, which are used as vegetables for human or animal food. They can be cooked in many different ways, including boiling, frying, and baking, and are used in many traditional dishes th ...

s. Ratios of naringenin to naringin vary among sources, as do enantiomeric ratios. The naringenin-7-glucoside form seems less bioavailable than the aglycol form. Grapefruit juice can provide much higher plasma concentrations of naringenin than orange juice. Also found in grapefruit is the related compound

kaempferol Kaempferol (3,4′,5,7-tetrahydroxyflavone) is a natural flavonol, a type of flavonoid, found in a variety of plants and plant-derived foods including kale, beans, tea, spinach, and broccoli. Kaempferol is a yellow crystalline solid with a meltin ...

, which has a hydroxyl group next to the ketone group. Naringenin can be absorbed from cooked tomato paste. There are 3.8 mg of naringenin in 150 grams of tomato paste.

Biosynthesis and metabolism

It is derived from

malonyl CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...

and 4-coumaroyl CoA. The latter is derived from phenylalanine. The resulting tetraketide is acted on by

chalcone synthase Chalcone synthase or naringenin-chalcone synthase (CHS) is an enzyme ubiquitous to higher plants and belongs to a family of polyketide synthase enzymes (PKS) known as type III PKS. Type III PKSs are associated with the production of chalcones, a ...

to give the chalcone that then undergoes ring-closure to naringenin. The enzyme naringenin 8-dimethylallyltransferase uses dimethylallyl diphosphate and (−)-(2''S'')-naringenin to produce diphosphate and 8-prenylnaringenin. ''

Cunninghamella elegans ''Cunninghamella elegans'' is a species of fungus in the genus '' Cunninghamella'' found in soil. It can be grown in Sabouraud dextrose broth, a liquid medium used for cultivation of yeasts and molds from liquid which are normally sterile. As ...

'', a fungal model organism of the mammalian metabolism, can be used to study the naringenin

sulfation Sulfation is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected less directly. Regardless of the mechanism, the ...

Potential biological effects

Alzheimer's disease

Naringenin is being researched as a potential treatment for Alzheimer's disease. Naringenin has been demonstrated to improve memory and reduce

amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the huma ...

and

tau protein The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintaining ...

s in a study using a mouse model of Alzheimer's disease. The effect is believed to be due to a protein present in neurons known as CRMP2 that naringenin binds to.

Antibacterial, antifungal, and antiviral

Naringenin has an antimicrobial effect on ''S. epidermidis'', as well as ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...

Bacillus subtilis ''Bacillus subtilis'', known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus ''Bacillus ...

Micrococcus luteus ''Micrococcus luteus'' is a Gram-positive, to Gram-variable, nonmotile, coccus, tetrad-arranging, pigmented, saprotrophic bacterium that belongs to the family Micrococcaceae. It is urease and catalase positive. An obligate aerobe, ''M. luteus' ...

,'' and ''

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

''. Further research has added evidence for antimicrobial effects against ''

Lactococcus lactis ''Lactococcus lactis'' is a Gram-positive bacterium used extensively in the production of buttermilk and cheese, but has also become famous as the first genetically modified organism to be used alive for the treatment of human disease. ''L. lact ...

'', ''

lactobacillus acidophilus ''Lactobacillus acidophilus'' (New Latin 'acid-loving milk-bacillus') is a rod-shaped, Gram-positive, homofermentative, anaerobic microbe first isolated from infant feces in the year 1900. The species is most commonly found in humans, specifically ...

'', '' Actinomyces naeslundii'', ''

Prevotella oralis ''Prevotella'' is a genus of Gram-negative bacteria. ''Prevotella'' spp. are members of the oral, List of microbiota species of the lower reproductive tract of women, vaginal, and gut microflora, gut microbiota and are often recovered from ana ...

'', '' Prevotella melaninogencia'', ''

Porphyromonas gingivalis ''Porphyromonas gingivalis'' belongs to the phylum ''Bacteroidota'' and is a nonmotile, Gram-negative, rod-shaped, anaerobic, pathogenic bacterium. It forms black colonies on blood agar. It is found in the oral cavity, where it is implicate ...

'', as well as yeasts such as ''

Candida albicans ''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is usu ...

Candida tropicalis ''Candida tropicalis'' is a species of yeast in the genus '' Candida''. It is a common pathogen in neutropenic hosts, in whom it may spread through the bloodstream to peripheral organs. For invasive disease, treatments include amphotericin B, ec ...

,'' and '' Candida krusei''. There is also evidence of antibacterial effects on ''

H. pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is thoug ...

'', though naringenin has not been shown to have any inhibition on

urease Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-contai ...

activity of the microbe. Naringenin has also been shown to reduce hepatitis C virus production by infected

hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...

s (liver cells) in cell culture. This seems to be secondary to naringenin's ability to inhibit the secretion of

very-low-density lipoprotein Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, low-density lipo ...

by the cells. The antiviral effects of naringenin are currently under clinical investigation. Reports of antiviral effects on

poliovirus A poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species '' Enterovirus C'', in the family of ''Picornaviridae''. There are three poliovirus serotypes: types 1, 2, and 3. Poliovirus is composed of a ...

es,

HSV-1 Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...

and HSV-2 have also been made, though replication of the viruses has not been inhibited. In ''in vitro'' experiments Naringenin also showed a strong antiviral activity against SARS-CoV-2.

Anti-inflammatory

Despite evidence of

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

activity of naringin, the anti-inflammatory activity of naringenin has been observed to be poor to nonexistent.

Antioxidant

Naringenin has been shown to have significant

antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...

properties. It has been shown to reduce oxidative damage to DNA ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

'' and in animal studies.

Anticancer

Cytotoxicity has been induced reportedly by naringenin in cancer cells from

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and sec ...

stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

, cervix,

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...

, and colon tissues, along with

leukaemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...

cells. The mechanisms behind inhibition of human

breast carcinoma Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a ...

growth have been examined, and two theories have been proposed. The first theory is that naringenin inhibits

aromatase Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze many ...

, thus reducing growth of the tumor. The second mechanism proposes that interactions with

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of the ...

s is the cause behind the modulation of growth. New derivatives of naringenin were found to be active against multidrug-resistant cancer.

Additional reading

*inhibitory effect on the human

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

isoform

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

resulting in delayed clearance of substances and protective effect against P4501A2-activated protoxicants. * * * * *Naringenin also produces

BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...

-dependent antidepressant-like effects in mice. * * *Naringenin has been reported to induce apoptosis in

preadipocytes Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. ...

. *Naringenin seems to protect LDLR-deficient mice from the obesity effects of a high-fat diet. *Naringenin lowers the plasma and hepatic

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

concentrations by suppressing HMG-CoA reductase and ACAT in rats fed a high-cholesterol diet. *Naringenin has been demonstrated to improve memory and reduce amyloid and tau proteins in a study using a mouse model of Alzheimer's disease.

References

{{Progesterone receptor modulators Aromatase inhibitors Delta-opioid receptor antagonists Flavanones Resorcinols Kappa-opioid receptor antagonists Mu-opioid receptor antagonists Progestogens Phytoestrogens Histidine decarboxylase inhibitors 3-Hydroxypropenals