Naringin
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Naringin is a
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 * Dichamanetin * Eriodictyol * Hesperetin * Hesperidin * Hom ...
-7-''O''-
glycoside In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. ...
between the flavanone
naringenin Naringenin is a flavanone from the flavonoid group of polyphenols. It is commonly found in citrus fruits, especially as the predominant flavonone in grapefruit. The fate and biological functions of naringenin in vivo are unknown, remaining und ...
and 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, ...
neohesperidose. The
flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...
naringin occurs naturally in
citrus fruit ''Citrus'' is a genus of flowering plant, flowering trees and shrubs in the family Rutaceae. Plants in the genus produce citrus fruits, including important crops such as Orange (fruit), oranges, Mandarin orange, mandarins, lemons, grapefruits, ...
s, especially in
grapefruit The grapefruit (''Citrus'' × ''paradisi'') is a subtropical citrus tree known for its relatively large, sour to semi-sweet, somewhat bitter fruit. The flesh of the fruit is segmented and varies in color from pale yellow to dark red. Grapefru ...
, where naringin is responsible for the fruit's bitter taste. In commercial grapefruit juice production, the enzyme
naringinase Naringinase is a debittering enzyme that is used in the commercial production of citrus juices. It breaks down the compound naringin that gives citrus juices its bitter taste. It is a multienzyme complex which possesses alpha-L-rhamnosidase and Β ...
can be used to remove the bitterness (debittering) created by naringin. In humans naringin is metabolized to the aglycone naringenin (not bitter) by naringinase present in the gut.


Structure

Naringin belongs to the
flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...
family. Flavonoids consist of 15 carbon atoms in 3 rings, 2 of which must be
benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...
rings connected by a 3 carbon chain. Naringin contains the basic flavonoid structure along with one rhamnose and one
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
unit attached to its
aglycone An aglycone (aglycon or genin) is the chemical compound remaining after the glycosyl group on a glycoside is replaced by a hydrogen atom. For example, the aglycone of a cardiac glycoside would be a steroid A steroid is an organic compoun ...
portion, called
naringenin Naringenin is a flavanone from the flavonoid group of polyphenols. It is commonly found in citrus fruits, especially as the predominant flavonone in grapefruit. The fate and biological functions of naringenin in vivo are unknown, remaining und ...
, at the 7-carbon position. The
steric hindrance Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivi ...
provided by the two sugar units makes naringin less potent than its
aglycone An aglycone (aglycon or genin) is the chemical compound remaining after the glycosyl group on a glycoside is replaced by a hydrogen atom. For example, the aglycone of a cardiac glycoside would be a steroid A steroid is an organic compoun ...
counterpart, naringenin.


Metabolism

In humans,
naringinase Naringinase is a debittering enzyme that is used in the commercial production of citrus juices. It breaks down the compound naringin that gives citrus juices its bitter taste. It is a multienzyme complex which possesses alpha-L-rhamnosidase and Β ...
is found in the liver and rapidly metabolizes naringin into
naringenin Naringenin is a flavanone from the flavonoid group of polyphenols. It is commonly found in citrus fruits, especially as the predominant flavonone in grapefruit. The fate and biological functions of naringenin in vivo are unknown, remaining und ...
. This happens in two steps: first, naringin is hydrolyzed by α-L-rhamnosidase activity of naringinase to rhamnose and
prunin Prunin is a flavanone glycoside found in immature citrus fruits and in tomatoes.Improved characterization of tomato polyphenols using liquid chromatography/electrospray ionization linear ion trap quadrupole Orbitrap mass spectrometry and liquid hr ...
. The prunin formed is then hydrolyzed by β-D-glucosidase activity of naringinase into naringenin and
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
.
Naringinase Naringinase is a debittering enzyme that is used in the commercial production of citrus juices. It breaks down the compound naringin that gives citrus juices its bitter taste. It is a multienzyme complex which possesses alpha-L-rhamnosidase and Β ...
is an enzyme that has a wide occurrence in nature and can be found in plants, yeasts, and fungi. It is commercially attractive due to its debittering properties.


Toxicity

The typical concentration of naringin in grapefruit juice is around 400 mg/L. The reported
LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a given substance. The value of LD50 for a substance is the dose requ ...
of naringin in rodents in 2000 mg/kg. Naringin inhibits some drug-metabolizing
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s, including
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
and
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 ...
, 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. However,
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
studies have also shown that naringin in grapefruit is not what causes the inhibitory effects associated with grapefruit juice. Naringin solution when compared to grapefruit solution produced much less inhibition of
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
. Furthermore,
bitter orange The bitter orange, sour orange, Seville orange, bigarade orange, or marmalade orange is the hybrid citrus tree species ''Citrus'' × ''aurantium'', and its fruit. It is native to Southeast Asia and has been spread by humans to many parts of th ...
juice, which contains considerably less naringin content than grapefruit juice, was found to produce the same level of inhibition of CYP3A4 as grapefruit juice. This would suggest that an inhibitor other than naringin, such as
furanocoumarin The furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. Most of the plant species found to contain furanocoumarins belong to a handful of plant families. The families Apiaceae and Rutacea ...
, which is also found in Seville oranges, may be at work. At the same time, naringenin is known to be a more potent inhibitor of CYP3A4/5 than naringin and in vitro studies have been unable to effectively convert naringin into naringenin. This leaves open the possibility that in vivo, naringin converted into naringenin by naringinase is what causes the inhibitory effect on CYP3A4. Due to the contradictory results of the effect of naringin it is hard to tell whether it is naringin itself or other components of grapefruit juice that cause drug-drug interaction and lead to its toxicity.


Uses


Commercial

When naringin is treated with
potassium hydroxide Potassium hydroxide is an inorganic compound with the formula K OH, and is commonly called caustic potash. Along with sodium hydroxide (NaOH), KOH is a prototypical strong base. It has many industrial and niche applications, most of which utili ...
or another strong base, and then catalytically hydrogenated, it becomes a naringin dihydrochalcone, a compound roughly 300–1800 times sweeter than sugar at threshold concentrations.


References


External links

* {{Glycosides Flavanone glycosides Flavonoids found in Rutaceae Bitter compounds