Chemistry:Naringenin

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Naringenin
Naringenin.svg
Naringenin 3D BS.png
Names
IUPAC name
(2S)-4′,5,7-Trihydroxyflavan-4-one
Systematic IUPAC name
(2S)-5,7-Dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one
Other names
Naringetol; Salipurol; Salipurpol
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
KEGG
UNII
Properties
C15H12O5
Molar mass 272.256 g·mol−1
Melting point 251 °C (484 °F; 524 K)[1]
475 mg/L[citation needed]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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.[2] Naringenin has demonstrated numerous biological activities, including anti-inflammatory properties, antioxidant activity and skin healing.[3][4][5][6] It is used as a cosmetic ingredient and dietary supplement.[7]

Structure

Naringenin has the skeleton structure of a flavanone with three hydroxy groups at the 4', 5, and 7 carbons. It may be found both in the aglycol form, naringenin, or in its glycosidic form, naringin, which has the addition of the disaccharide neohesperidose attached via a glycosidic linkage at carbon 7.

Like the majority of flavanones, naringenin has a single chiral center at carbon 2, although the optical purity is variable.[8][9] Racemization of (S)-(-)-naringenin has been shown to occur fairly quickly.[10]

Sources and bioavailability

Naringenin and its glycoside has been found in a variety of herbs and fruits, including grapefruit,[11] bergamot,[12] sour orange,[13] tart cherries,[5] tomatoes,[14][15] cocoa,[16] Greek oregano,[17] water mint,[18] as well as in beans.[19] Ratios of naringenin to naringin vary among sources,[14] as do enantiomeric ratios.[9]

The naringenin-7-glucoside form seems less bioavailable than the aglycol form.[20]

Grapefruit juice can provide much higher plasma concentrations of naringenin than orange juice.[21] Also found in grapefruit is the related compound kaempferol, 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.[22]

Biosynthesis and metabolism

It is derived from malonyl CoA and 4-coumaroyl CoA. The latter is derived from phenylalanine. The resulting tetraketide is acted on by chalcone synthase to give the chalcone that then undergoes ring-closure to naringenin.[23]

The enzyme naringenin 8-dimethylallyltransferase uses dimethylallyl diphosphate and (−)-(2S)-naringenin to produce diphosphate and 8-prenylnaringenin. Cunninghamella elegans, a fungal model organism of the mammalian metabolism, can be used to study the naringenin sulfation.[24]

Potential biological effects

Studies show naringenin has numerous biological activities, including anti-inflammatory, antioxidant, antibacterial, antiviral and anticancer. It is deemed safe for both topical and ingestible use in healthy adults.[7]

Anti-inflammatory

Naringenin’s anti-inflammatory benefits have been well established with multiple in vitro and in vivo studies, revealing it effectively suppresses proinflammatory factors, cytokine and chemokine expressions in inflammation.[3] When taken orally, it has also been shown to reduce inflammatory pain.[25]

Antioxidant

Naringenin has been shown to have significant antioxidant properties.[26][27] It has been shown to reduce oxidative damage to DNA in vitro and in animal studies.[28][29] When consumed it has been shown to increase antioxidant markers superoxide dismutase and glutathione.[6]

Antibacterial, antifungal, and antiviral

Naringenin has an antimicrobial effect on S. epidermidis, as well as Staphylococcus aureus, Bacillus subtilis, Micrococcus luteus, and Escherichia coli.[30] Further research has added evidence for antimicrobial effects against Lactococcus lactis,[31] lactobacillus acidophilus, Actinomyces naeslundii, Prevotella oralis, Prevotella melaninogencia, Porphyromonas gingivalis,[32] as well as yeasts such as Candida albicans, Candida tropicalis, and Candida krusei.[33] There is also evidence of antibacterial effects on H. pylori, though naringenin has not been shown to have any inhibition on urease activity of the microbe.[34]

Naringenin has also been shown to reduce hepatitis C virus production by infected hepatocytes (liver cells) in cell culture. This seems to be secondary to naringenin's ability to inhibit the secretion of very-low-density lipoprotein by the cells.[35] The antiviral effects of naringenin are currently under clinical investigation.[36] Reports of antiviral effects on polioviruses, HSV-1 and HSV-2 have also been made, though replication of the viruses has not been inhibited.[37][38] In in vitro experiments Naringenin also showed a strong antiviral activity against SARS-CoV-2. [39]

Skin Healing

When used in topical formulations, naringenin has been shown to be an anti-inflammatory with skin barrier restoration and antioxidant activities.

UVB radiation is very high energy frequency and wreak havoc on the top layers of the skin by damaging the skin cells and causing DNA mutations that can lead to melanoma and other skin cancers.[40] Naringenin has been proven to reduce UVB-induced skin damage, as well as showing efficacy against oxidative stress and improvement in wound healing.[4][41][6]

Naringenin has also been studied on inflammatory skin conditions such as atopic dermatitis and psoriasis.[3][42][43] For atopic dermatitis, naringenin was found to sharply suppress inflammatory levels and alleviate symptoms and may suppress the development of atopic dermatitis like skin lesions.[3][42] In psoriasis, naringenin has been studied to reduce inflammation in psoriatic plaques.[43]

Anticancer

Cytotoxicity has been reduced reportedly by naringenin in cancer cells from breast, stomach, liver, cervix, pancreas, and colon tissues, along with leukaemia cells.[44][45] The mechanisms behind inhibition of human breast carcinoma growth have been examined, and two theories have been proposed.[46] The first theory is that naringenin inhibits aromatase, thus reducing growth of the tumor.[47] The second mechanism proposes that interactions with estrogen receptors is the cause behind the modulation of growth.[48] New derivatives of naringenin were found to be active against multidrug-resistant cancer.[49]

Fatty Liver Disease

Naringenin may have some benefits for non-alcoholic fatty liver disease. It was proven to reduce hepatic lipid accumulation and inflammation in the livers of mice with non-alcoholic fatty liver disease.[50]

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 and tau proteins in a study using a mouse model of Alzheimer's disease.[51][52] The effect is believed to be due to a protein present in neurons known as CRMP2 that naringenin binds to.[53]

Safety

Naringenin has been deemed safe to apply topically and can also be ingested safely by healthy adults in doses of 150 to 900 mg doses, with 300 mg of naringenin twice a day likely to elicit physiological effect.[7]

References

  1. ↑ Template:HMDB
  2. ↑ "Bioavailability of the flavanone naringenin and its glycosides in rats". American Journal of Physiology. Gastrointestinal and Liver Physiology 279 (6): G1148–G1154. December 2000. doi:10.1152/ajpgi.2000.279.6.G1148. PMID 11093936. https://hal.inrae.fr/hal-02694848/file/67273_20100906040812887_1.pdf. 
  3. ↑ 3.0 3.1 3.2 3.3 "Naringenin ameliorates skin inflammation and accelerates phenotypic reprogramming from M1 to M2 macrophage polarization in atopic dermatitis NC/Nga mouse model". Experimental Dermatology 25 (5): 404–407. May 2016. doi:10.1111/exd.12962. PMID 26836240. 
  4. ↑ 4.0 4.1 "Topical Formulation Containing Naringenin: Efficacy against Ultraviolet B Irradiation-Induced Skin Inflammation and Oxidative Stress in Mice". PLOS ONE 11 (1): e0146296. 2016-01-07. doi:10.1371/journal.pone.0146296. PMID 26741806. Bibcode: 2016PLoSO..1146296M. 
  5. ↑ 5.0 5.1 "Antioxidant polyphenols from tart cherries (Prunus cerasus)". Journal of Agricultural and Food Chemistry 47 (3): 840–844. March 1999. doi:10.1021/jf980936f. PMID 10552377. 
  6. ↑ 6.0 6.1 6.2 "Naringenin improves the healing process of thermally-induced skin damage in rats". The Journal of International Medical Research 45 (2): 570–582. April 2017. doi:10.1177/0300060517692483. PMID 28415935. 
  7. ↑ 7.0 7.1 7.2 "Safety and pharmacokinetics of naringenin: A randomized, controlled, single-ascending-dose clinical trial". Diabetes, Obesity & Metabolism 22 (1): 91–98. January 2020. doi:10.1111/dom.13868. PMID 31468636. 
  8. ↑ "Methods of analysis and separation of chiral flavonoids". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 848 (2): 159–181. April 2007. doi:10.1016/j.jchromb.2006.10.052. PMID 17113835. 
  9. ↑ 9.0 9.1 "Pharmacokinetics of selected chiral flavonoids: hesperetin, naringenin and eriodictyol in rats and their content in fruit juices". Biopharmaceutics & Drug Disposition 29 (2): 63–82. March 2008. doi:10.1002/bdd.588. PMID 18058792. 
  10. ↑ "Analysis of enantiomeric flavanones in plant extracts by high-performance liquid chromatography on a cellulose triacetate based chiral stationary phase" (in en). Chromatographia 32 (1–2): 69–72. July 1991. doi:10.1007/BF02262470. ISSN 0009-5893. 
  11. ↑ "Content of CYP3A4 inhibitors, naringin, naringenin and bergapten in grapefruit and grapefruit juice products". Pharmaceutica Acta Helvetiae 74 (4): 379–385. April 2000. doi:10.1016/S0031-6865(99)00062-X. PMID 10812937. 
  12. ↑ "Flavonoid composition of Citrus juices". Molecules 12 (8): 1641–1673. August 2007. doi:10.3390/12081641. PMID 17960080. 
  13. ↑ "Chiral separation of diastereomeric flavanone-7-O-glycosides in citrus by capillary electrophoresis". Electrophoresis 24 (15): 2716–2722. August 2003. doi:10.1002/elps.200305486. PMID 12900888. 
  14. ↑ 14.0 14.1 "Polyphenol pattern and antioxidant activity of different tomato lines and cultivars". Annals of Nutrition & Metabolism 47 (2): 64–69. 2003-01-01. doi:10.1159/000069277. PMID 12652057. 
  15. ↑ "Changes in the polyphenol profile of tomato juices processed by pulsed electric fields". Journal of Agricultural and Food Chemistry 60 (38): 9667–9672. September 2012. doi:10.1021/jf302791k. PMID 22957841. 
  16. ↑ "Liquid chromatographic/electrospray ionization tandem mass spectrometric study of the phenolic composition of cocoa (Theobroma cacao)". Journal of Mass Spectrometry 38 (1): 35–42. January 2003. doi:10.1002/jms.395. PMID 12526004. Bibcode: 2003JMSp...38...35S. 
  17. ↑ "LC-UV-solid-phase extraction-NMR-MS combined with a cryogenic flow probe and its application to the identification of compounds present in Greek oregano". Analytical Chemistry 75 (22): 6288–6294. November 2003. doi:10.1021/ac0347819. PMID 14616013. 
  18. ↑ "Isolation of the MAO-inhibitor naringenin from Mentha aquatica L". Journal of Ethnopharmacology 117 (3): 500–502. May 2008. doi:10.1016/j.jep.2008.02.015. PMID 18372132. 
  19. ↑ "Effects of flavonoids released naturally from bean (Phaseolus vulgaris) on nodD-regulated gene transcription in Rhizobium leguminosarum bv. phaseoli". Molecular Plant-Microbe Interactions 5 (3): 199–203. 1992-05-01. doi:10.1094/mpmi-5-199. PMID 1421508. 
  20. ↑ "Interactions of the flavonoid naringenin in the gastrointestinal tract and the influence of glycosylation". Biochemical and Biophysical Research Communications 265 (2): 410–415. November 1999. doi:10.1006/bbrc.1999.1695. PMID 10558881. 
  21. ↑ "Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice". The Journal of Nutrition 131 (2): 235–241. February 2001. doi:10.1093/jn/131.2.235. PMID 11160539. 
  22. ↑ "Naringenin from cooked tomato paste is bioavailable in men". The Journal of Nutrition 132 (11): 3349–3352. November 2002. doi:10.1093/jn/132.11.3349. PMID 12421849. 
  23. ↑ "Characterization of Stilbene Synthase Genes in Mulberry (Morus atropurpurea) and Metabolic Engineering for the Production of Resveratrol in Escherichia coli". Journal of Agricultural and Food Chemistry 65 (8): 1659–1668. March 2017. doi:10.1021/acs.jafc.6b05212. PMID 28168876. 
  24. ↑ "Sulfation of naringenin by Cunninghamella elegans". Phytochemistry 53 (2): 209–212. January 2000. doi:10.1016/S0031-9422(99)00487-2. PMID 10680173. Bibcode: 2000PChem..53..209I. 
  25. ↑ "Naringenin reduces inflammatory pain in mice". Neuropharmacology 105: 508–519. June 2016. doi:10.1016/j.neuropharm.2016.02.019. PMID 26907804. 
  26. ↑ "Changes in plasma lipid and antioxidant activity in rats as a result of naringin and red grapefruit supplementation". Journal of Agricultural and Food Chemistry 53 (8): 3223–3228. April 2005. doi:10.1021/jf058014h. PMID 15826081. 
  27. ↑ "Antioxidant activity of citrus limonoids, flavonoids, and coumarins". Journal of Agricultural and Food Chemistry 53 (6): 2009–2014. March 2005. doi:10.1021/jf0484632. PMID 15769128. 
  28. ↑ "Biochemical and Molecular Mechanisms of Radioprotective Effects of Naringenin, a Phytochemical from Citrus Fruits". Journal of Agricultural and Food Chemistry 64 (8): 1676–1685. March 2016. doi:10.1021/acs.jafc.5b05067. PMID 26881453. 
  29. ↑ "Influence of naringin on ferric iron induced oxidative damage in vitro". Clinica Chimica Acta; International Journal of Clinical Chemistry 347 (1–2): 189–197. September 2004. doi:10.1016/j.cccn.2004.04.022. PMID 15313158. 
  30. ↑ "Antimicrobial effects of Finnish plant extracts containing flavonoids and other phenolic compounds". International Journal of Food Microbiology 56 (1): 3–12. May 2000. doi:10.1016/S0168-1605(00)00218-X. PMID 10857921. 
  31. ↑ "Antimicrobial activity of flavonoids extracted from bergamot (Citrus bergamia Risso) peel, a byproduct of the essential oil industry". Journal of Applied Microbiology 103 (6): 2056–2064. December 2007. doi:10.1111/j.1365-2672.2007.03456.x. PMID 18045389. 
  32. ↑ "In vitro antimicrobial activity of propolis samples from different geographical origins against certain oral pathogens". Anaerobe 13 (3–4): 140–145. 2007-06-01. doi:10.1016/j.anaerobe.2007.02.001. PMID 17475517. 
  33. ↑ "Chemical compositions and antimicrobial activities of four different Anatolian propolis samples". Microbiological Research 160 (2): 189–195. 2005-04-25. doi:10.1016/j.micres.2005.01.002. PMID 15881836. 
  34. ↑ "In vitro anti-Helicobacter pylori activity of some flavonoids and their metabolites". Planta Medica 65 (5): 442–443. June 1999. doi:10.1055/s-2006-960805. PMID 10454900. 
  35. ↑ "Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin". Hepatology 47 (5): 1437–1445. May 2008. doi:10.1002/hep.22197. PMID 18393287. 
  36. ↑ "A Pilot Study of the Grapefruit Flavonoid Naringenin for HCV Infection - Full Text View - ClinicalTrials.gov". http://clinicaltrials.gov/ct2/show/NCT01091077?term=naringenin&rank=1. 
  37. ↑ "Inhibition of virus multiplication and alteration of cyclic AMP level in cell cultures by flavonoids". Experientia 41 (7): 930–931. July 1985. doi:10.1007/BF01970018. PMID 2989000. 
  38. ↑ "Antiherpetic activities of flavonoids against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro". Archives of Pharmacal Research 28 (11): 1293–1301. November 2005. doi:10.1007/BF02978215. PMID 16350858. 
  39. ↑ "Naringenin is a powerful inhibitor of SARS-CoV-2 infection in vitro". Pharmacological Research 163: 105255. January 2021. doi:10.1016/j.phrs.2020.105255. PMID 33096221. 
  40. ↑ "What's the difference between UVA and UVB rays?" (in en). https://www.mdanderson.org/publications/focused-on-health/what-s-the-difference-between-uva-and-uvb-rays-.h15-1592991.html. 
  41. ↑ "Accelerating healing of excisional wound with alginate hydrogel containing naringenin in rat model". Drug Delivery and Translational Research 11 (1): 142–153. February 2021. doi:10.1007/s13346-020-00731-6. PMID 32086788. 
  42. ↑ 42.0 42.1 "The inhibitory effect of naringenin on atopic dermatitis induced by DNFB in NC/Nga mice". Life Sciences 93 (15): 516–524. October 2013. doi:10.1016/j.lfs.2013.07.027. PMID 23933131. 
  43. ↑ 43.0 43.1 "Development of flavanone and its derivatives as topical agents against psoriasis: The prediction of therapeutic efficiency through skin permeation evaluation and cell-based assay". International Journal of Pharmaceutics 581: 119256. May 2020. doi:10.1016/j.ijpharm.2020.119256. PMID 32220586. 
  44. ↑ "Inhibitory effects of naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice". Biological & Pharmaceutical Bulletin 28 (3): 527–530. March 2005. doi:10.1248/bpb.28.527. PMID 15744083. 
  45. ↑ "Identification of potential therapeutic target of naringenin in breast cancer stem cells inhibition by bioinformatics and in vitro studies". Saudi Pharmaceutical Journal 29 (1): 12–26. January 2021. doi:10.1016/j.jsps.2020.12.002. PMID 33603536. 
  46. ↑ "Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices". Nutrition and Cancer 26 (2): 167–181. 1996-01-01. doi:10.1080/01635589609514473. PMID 8875554. 
  47. ↑ "(Anti)estrogenic effects of phytochemicals on human primary mammary fibroblasts, MCF-7 cells and their co-culture". Toxicology and Applied Pharmacology 221 (3): 372–383. June 2007. doi:10.1016/j.taap.2007.03.016. PMID 17482226. 
  48. ↑ "Naringenin inhibits glucose uptake in MCF-7 breast cancer cells: a mechanism for impaired cellular proliferation". Breast Cancer Research and Treatment 85 (2): 103–110. May 2004. doi:10.1023/B:BREA.0000025397.56192.e2. PMID 15111768. 
  49. ↑ "Optimizing the flavanone core toward new selective nitrogen-containing modulators of ABC transporters" (in EN). Future Medicinal Chemistry 10 (7): 725–741. April 2018. doi:10.4155/fmc-2017-0228. PMID 29570361. 
  50. ↑ "Non-alcoholic fatty liver disease". Oxford Medicine Online. September 2018. doi:10.1093/med/9780198759928.003.0061. http://dx.doi.org/10.1093/med/9780198759928.003.0061. 
  51. ↑ "Naringenin improves learning and memory in an Alzheimer's disease rat model: Insights into the underlying mechanisms". European Journal of Pharmacology 764: 195–201. October 2015. doi:10.1016/j.ejphar.2015.07.001. PMID 26148826. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-120716. 
  52. ↑ "Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression". Phytotherapy Research 33 (4): 1114–1121. April 2019. doi:10.1002/ptr.6305. PMID 30768735. 
  53. ↑ "A Systematic Strategy for Discovering a Therapeutic Drug for Alzheimer's Disease and Its Target Molecule". Frontiers in Pharmacology 8: 340. 19 June 2017. doi:10.3389/fphar.2017.00340. PMID 28674493. 

Further reading



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