Naringin

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Naringin
Naringin.svg
Naringin 3D BS.png
Names
IUPAC name
(2S)-4′,5-Dihydroxy-7-[α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyloxy]flavan-4-one
Systematic IUPAC name
(2S)-7-{[(2S,3R,4S,5S,6R)-4,5-Dihydroxy-6-(hydroxymethyl)-3-{[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}oxan-2-yl]oxy}-5-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one
Other names
Naringin
Naringoside
4′,5,7-Trihydroxyflavanone-7-rhamnoglucoside
Naringenin 7-O-neohesperidoside
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.030.502 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C27H32O14/c1-10-20(32)22(34)24(36)26(37-10)41-25-23(35)21(33)18(9-28)40-27(25)38-13-6-14(30)19-15(31)8-16(39-17(19)7-13)11-2-4-12(29)5-3-11/h2-7,10,16,18,20-30,32-36H,8-9H2,1H3/t10-,16+,18-,20+,21-,22+,23+,24-,25-,26-,27-/m1/s1 Yes check.svgY
    Key: DFPMSGMNTNDNHN-CSIAVLANSA-N Yes check.svgY
  • InChI=1/C27H32O14/c1-10-20(32)22(34)24(36)26(37-10)41-25-23(35)21(33)18(9-28)40-27(25)38-13-6-14(30)19-15(31)8-16(39-17(19)7-13)11-2-4-12(29)5-3-11/h2-7,10,16,18,20-30,32-36H,8-9H2,1H3/t10-,16+,18-,20+,21-,22+,23+,24-,25-,26-,27-/m1/s1
    Key: DFPMSGMNTNDNHN-CSIAVLANBN
  • O=C4c5c(O)cc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O[C@H]1O[C@@H]([C@H](O)[C@H](O)[C@H]1O)C)cc5O[C@H](c3ccc(O)cc3)C4
Properties
C27H32O14
Molar mass 580.54 g/mol
Melting point 166 °C (331 °F; 439 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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's bitter taste. In commercial grapefruit juice production, the enzyme naringinase can be used to remove the bitterness (debittering) created by naringin. [1] In humans naringin is metabolized to the aglycone naringenin (not bitter) by naringinase present in the gut.

Contents

Structure

Naringin belongs to the flavonoid family. Flavonoids consist of 15 carbon atoms in 3 rings, 2 of which must be benzene rings connected by a 3 carbon chain. Naringin contains the basic flavonoid structure along with one rhamnose and one glucose unit attached to its aglycone portion, called naringenin, at the 7-carbon position. The steric hindrance provided by the two sugar units makes naringin less potent than its aglycone counterpart, naringenin. [2]

Flavonoid basis.svg

Metabolism

In humans, naringinase is found in the liver and rapidly metabolizes naringin into naringenin. This happens in two steps: first, naringin is hydrolyzed by α-L-rhamnosidase activity of naringinase to rhamnose and prunin. The prunin formed is then hydrolyzed by β-D-glucosidase activity of naringinase into naringenin and glucose. [3] Naringinase 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. [3]

Toxicity

The typical concentration of naringin in grapefruit juice is around 400 mg/L. [4] The reported LD50 of naringin in rodents in 2000 mg/kg. [5]

Naringin inhibits some drug-metabolizing cytochrome P450 enzymes, including CYP3A4 and CYP1A2, which may result in drug-drug interactions. [6] 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. [7]

However, in vitro 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. [8] Furthermore, bitter orange 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, which is also found in Seville oranges, may be at work. [8] At the same time, naringenin is known to be a more potent inhibitor of CYP3A4/5 than naringin [9] 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. [8] 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 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. [10]

Related Research Articles

<span class="mw-page-title-main">Grapefruit</span> Citrus fruit

The grapefruit is a subtropical citrus tree known for its relatively large, sour to semi-sweet, somewhat bitter fruit. The interior flesh is segmented and varies in color from pale yellow to dark pink/red.

<span class="mw-page-title-main">Glycoside</span> Molecule in which a sugar is bound to another functional group

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. These can be activated by enzyme hydrolysis, which causes the sugar part to be broken off, making the chemical available for use. Many such plant glycosides are used as medications. Several species of Heliconius butterfly are capable of incorporating these plant compounds as a form of chemical defense against predators. In animals and humans, poisons are often bound to sugar molecules as part of their elimination from the body.

<span class="mw-page-title-main">Cytochrome P450</span> Class of enzymes

Cytochromes P450 are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown. In 1963, Estabrook, Cooper, and Rosenthal described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.

<span class="mw-page-title-main">CYP3A4</span> Enzyme that metabolizes substances by oxidation

Cytochrome P450 3A4 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 oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.

<span class="mw-page-title-main">Drug interaction</span> Change in the action or side effects of a drug caused

In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug-food interaction is the effect of grapefruit in the metabolism of drugs.

<span class="mw-page-title-main">Grapefruit juice</span> Fruit juice from grapefruits

Grapefruit juice is the juice from grapefruits. It is rich in vitamin C and ranges from sweet-tart to very sour. Variations include white grapefruit, pink grapefruit and ruby red grapefruit juice.

<span class="mw-page-title-main">Quercetin</span> Chemical compound

Quercetin is a plant flavonol from the flavonoid group of polyphenols. It is found in many fruits, vegetables, leaves, seeds, and grains; capers, red onions, and kale are common foods containing appreciable amounts of it. It has a bitter flavor and is used as an ingredient in dietary supplements, beverages, and foods.

<span class="mw-page-title-main">Naringenin</span> Chemical compound

Naringenin is a flavanone from the flavonoid group of polyphenols and is commonly found in a variety of citrus fruits and is the predominant flavonone in grapefruit. Naringenin has demonstrated numerous biological activities, including anti-inflammatory properties, antioxidant activity and skin healing. It is used as a cosmetic ingredient and dietary supplement.

<span class="mw-page-title-main">Rutin</span> Chemical compound

Rutin is the glycoside combining the flavonol quercetin and the disaccharide rutinose. It is a flavonoid glycoside found in a wide variety of plants, including citrus.

<span class="mw-page-title-main">Hesperidin</span> Chemical compound

Hesperidin is a flavanone glycoside found in citrus fruits. Its aglycone is hesperetin. Its name is derived from the word "hesperidium", for fruit produced by citrus trees.

<span class="mw-page-title-main">Hesperetin</span> Chemical compound

Hesperetin is the 4'-methoxy derivative of eriodictyol, a flavanone. Hesperetin's 7-O-glycoside, hesperidin, is a naturally occurring flavanon-glycoside, the main flavonoid in lemons and sweet oranges. Hesperetin are not found to a significant extent in Citrus spp.

<span class="mw-page-title-main">CYP1A2</span> Enzyme in the human body

Cytochrome P450 1A2, 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.

<span class="mw-page-title-main">Grapefruit–drug interactions</span> Drug interactions with grapefruit juice

Some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects. The effect is most studied with grapefruit and grapefruit juice, but similar effects have been observed with certain other citrus fruits.

The erythromycin breath test (ERMBT) is a method used to measure metabolism (oxidation and elimination from the system) by a part of the cytochrome P450 system. Erythromycin produces 14CO2, and this 14CO2 can be measured to study drugs that interact with the cytochrome P450 system. Erythromycin is tagged with carbon-14 and given as an intravenous injection; after 20 minutes the subject blows up a balloon and the carbon dioxide exhaled that is tagged with carbon-14 shows the activity of the CYP3A4 isoenzyme on the erythromycin. ERMBT can be used to determine how drugs that the CYP3A4 isoenzyme metabolizes will function in a given individual.

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 beta glucosidase active centers. The E.C. No.(EC 3.2.1.40) of the naringinase and rhamnosidase are the same. First rhamnosidase breaks naringin into prunin and rhamnose. Lastly glucosidase breaks prunin into glucose and naringenin, a flavorless flavanone also found in various citrus.

<span class="mw-page-title-main">Flavanone</span>

The flavanones, a type of flavonoids, are various aromatic, colorless ketones derived from flavone that often occur in plants as glycosides.

<span class="mw-page-title-main">Bergamottin</span> Chemical compound

Bergamottin (5-geranoxypsoralen) is a natural furanocoumarin found in the pulp of pomelos and grapefruits. It is also found in the peel and pulp of the bergamot orange, from which it was first isolated and from which its name is derived.

In enzymology, a flavanone 7-O-beta-glucosyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Chalconoid</span> Natural phenols related to chalcone

Chalconoids, also known as chalcones, are natural phenols derived from chalcone. They form the central core for a variety of important biological compounds.

<span class="mw-page-title-main">Prunin</span> Chemical compound

Prunin is a flavanone glycoside found in immature citrus fruits and in tomatoes. Its aglycone form is called naringenin.

References

  1. Dicosimo R, McAuliffe J, Poulose AJ, Bohlmann G (2013). "Industrial use of immobilized enzymes". Chemical Society Reviews. 42 (15): 6437–6474. doi:10.1039/c3cs35506c. PMID   23436023.
  2. Alam MA, Subhan N, Rahman MM, Uddin SJ, Reza HM, Sarker SD (July 2014). "Effect of Citrus Flavonoids, Naringin and Naringenin, on Metabolic Syndrome and Their Mechanisms of Action". Advances in Nutrition. 5 (4): 404–417. doi:10.3945/an.113.005603. ISSN   2156-5376. PMC   4085189 . PMID   25022990.
  3. 1 2 Ribeiro MH (June 2011). "Naringinases: occurrence, characteristics, and applications". Applied Microbiology and Biotechnology. 90 (6): 1883–1895. doi:10.1007/s00253-011-3176-8. ISSN   0175-7598. PMID   21544655. S2CID   1653069.
  4. Yusof S (January 1990). "Naringin content in local citrus fruits". Food Chemistry. 37 (2): 113–121. doi:10.1016/0308-8146(90)90085-I.
  5. "Naringin: Safety and Acute toxicity". www.mdidea.com. Retrieved 2017-05-08.
  6. Fuhr U, Kummert AL (1995). "The fate of naringin in humans: a key to grapefruit juice-drug interactions?". Clinical Pharmacology & Therapeutics. 58 (4): 365–373. doi:10.1016/0009-9236(95)90048-9. PMID   7586927. S2CID   21372946.
  7. "Fruit juice 'could affect drugs'". BBC News. August 20, 2008. Retrieved 2022-05-28.
  8. 1 2 3 Edwards DJ, Bernier SM (January 1996). "Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice". Life Sciences. 59 (13): 1025–1030. doi:10.1016/0024-3205(96)00417-1. ISSN   0024-3205. PMID   8809221.
  9. Lundahl J, Regårdh CG, Edgar B, Johnsson G (January 1997). "Effects of grapefruit juice ingestion—pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men". European Journal of Clinical Pharmacology. 52 (2): 139–145. doi:10.1007/s002280050263. ISSN   0031-6970. PMID   9174684. S2CID   22705973.
  10. Tomasik P, ed. (2004). Chemical and Functional Properties of Food Saccharides. Boca Raton: CRC Press. p. 389. ISBN   978-0-84-931486-5. LCCN   2003053186.