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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 83-90

Biodynamic activities of ellagic acid: A dietary polyphenol


1 Natural Cum Advance Synthetic Lab, Department of Pharmacy, Tripura University (A Central University), Agartala, Tripura, India
2 Natural Cum Advance Synthetic Lab, Department of Pharmacy, Tripura University (A Central University), Agartala, Tripura; Department of Pharmaceutical Chemistry, Srikrupa Institute of Pharmaceutical Sciences, Siddipet, Telangana, India

Date of Submission22-Jul-2019
Date of Decision03-Sep-2019
Date of Acceptance06-Nov-2020
Date of Web Publication02-Apr-2020

Correspondence Address:
Kuntal Manna
Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Agartala - 799 022, Tripura
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_32_19

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  Abstract 


Plant polyphenols are fast-growing food products for the health beneficial properties. Ellagic acid (EA) is a fused four-ring polyphenol. It is present in the form of ellagitannin in plants. A significant quantity of EA was found in raspberry, blackberry, strawberry, cloudberry, and pomegranate. The present article provides ample information on the biological sources from fruits, its biotransformation, bioavailability, and metabolism along with biofunctions on human health.

Keywords: Biodegradation, biological activity, ellagic acid, metabolism, polyphenols


How to cite this article:
Debnath B, Singh WS, Das M, Goswami S, Manna K. Biodynamic activities of ellagic acid: A dietary polyphenol. J Nat Sci Med 2020;3:83-90

How to cite this URL:
Debnath B, Singh WS, Das M, Goswami S, Manna K. Biodynamic activities of ellagic acid: A dietary polyphenol. J Nat Sci Med [serial online] 2020 [cited 2020 Oct 20];3:83-90. Available from: https://www.jnsmonline.org/text.asp?2020/3/2/83/278238




  Introduction Top


Ellagic acid (EA) belongs to the class of plant polyphenols. It plays an important role in food science as a dietary polyphenol consisting of a dimer of lactonized gallic acid. It is widely biosynthesized in plants as a secondary metabolite.[1] Dietary polyphenols have a vital impact on human health. Tannins are water-soluble polyphenols, which are commonly found in developed herbaceous and woody plants that have protein precipitation ability.[2] They can be classified into two categories: hydrolysable and nonhydrolysable (condense) tannins. Hydrolysable tannins consist of large groups of compounds belonging to ellagitannins (ETs). ETs are ester of phenolic acid and a polyol, usually glucose. ETs on hydrolysis with acids or bases give hexahydroxydiphenic acid, which rapidly lactonizes to EA. Therefore, ETs are composite derivatives of EA.[3],[4]

Since 1980, much has been known about the clinical attributes of EA, but comparatively little is known about the physiological, biodegradation, and metabolic aspects of EA.[5],[6],[7] It was found to be potential anticarcinogen, radical scavenger and has many other biological activities. Regular intake of it as a dietary substituent may minimize cancer risk.[8] In this review, we summarized the biotransformation and metabolic pathway of EA formation, sources of EA, and its biological activities in the following sections.


  Common Biological Sources of Ellagic Acid Top


In the plant kingdom, an abundant quantity of EA is present in berries (especially raspberries, blackberries, and strawberries),[9] pomegranates, and grapes.[10] The common biological sources of EA are represented in [Table 1].
Table 1: The common biological sources of ellagic acid

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  Biodegradation of Ellagitannins to Ellagic Acid Top


The biodegradation process of ETs is important to study the enzymatic mechanism responsible for the production of EA. With the help of different enzymes, biodegradation of ETs occurs by both hydrolysis and oxidation.[15] Ascacio-Valdés et al. studied the fungal biodegradation pathway of ETs in Aspergillus niger GH1. Cellulase, polyphenol oxidase, β-glucosidase, tannase, and xylanase enzymes were used for the enzymatic biodegradation of ETs, but the study was not conclusive to show the difference in enzyme activity.[16]

To overcome this problem, Ascacio-Valdés et al. initially studied the fungal (Aspergillus niger GH1) biodegradation pathway of ETs [Figure 1]. They revealed that ellagitannase or ET acyl hydrolase is the active starting fungal enzyme in this pathway. Ellagitannase was found to hydrolyze ester bonds of ETs and release EA subsequently. Petri-plate method was used to determine the paramount time for ellagitannase activity.[17]
Figure 1: Biodegradation pathway of ellagitannins to ellagic acid in fungus Aspergillus niger GH1

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  Bioavailability and Metabolism of Ellagic Acid Top


The bioavailability of EA depends on the acidic environment (pH 1.8–2.0) of the gastrointestinal tract. It was shown that EA is bioavailable in the presence of gastric enzymes such as pepsin, rennin, and gastric lipase in a differentin vitro study.[18] In a further study, pancreatic enzymes and bile salts were unable to convert ETs into EA by hydrolysis. The pH 7.0–7.3 was found to be the optimum range where ETs conversion rate into EA was approximately 100%, and in this condition, bioavailability of EA was considered maximal.[19]

Gut microbiota was found to influence EA bioavailability through aglycones which were released from the O-glycosides by hydrolytic process and hepatic O-glucuronidation. Urolithins are the metabolites of EA formed during the metabolism through gut microbiota, display a potential influence on biological responses.[20] Urolithins constitute an entire metabolite family, which are formed by the opening and decarboxylation of a single lactone ring of EA followed by the elimination of hydroxyl groups at different positions. The metabolism pathway of EA in the gut microbiota is illustrated in [Figure 2], in which EA or extract containing EA was orally administered on experimental volunteers.
Figure 2: Common microflora metabolites of ellagic acid

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EA metabolites were identified as urolithin A, urolithin B, and urolithin C. Isourolithin A, urolithin D, urolithin E, urolithin M6, and urolithin M7 were also found as important metabolites. All of these metabolites were observed in both plasma and urine.[21]

Ma et al. studied the intravenous bioavailability and metabolism of purified ET for the first time. They isolated a pure ET from the ethanolic extract of Pelargonium capitatum, and the isolate was injected in the tail vein of male Sprague-Dawley rats to study its metabolism [Figure 3]. Ion trap mass spectrometry coupled with high-performance liquid chromatography was used for the identification of metabolites.[22]
Figure 3: The proposed metabolism pathway of ellagitannin

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  Biological Activity of Ellagic Acid Top


Anti-inflammatory activity

Anti-inflammatory activity evaluation of pomegranate (Punica granatum) extract containing EA was performed byin vivo andin vitro methods. Anin vivo study showed a significant reduction in the ulcer index in ethanol-induced gastritis in rats by pomegranate fruit rind methanolic extract. EA inhibited leukocyte and accession to the endothelium by the inhibition of reactive oxygen species (ROS) generation. EA considerably upregulated the mucosal prostaglandin E2 (PGE2) level and reduced significantly mucosal myeloperoxidase activity after 3 days of treatment. The expression of gastric cyclooxygenase-1 was significantly depleted. Treatment with EA (10 mg/kg) on the rats showed a significantly lower level of tumor necrosis factor-alpha (TNF-α) subjected to ethanol-induced ulcer than the ethanol-treated group (versus pg/mL, respectively.).[23]

Lipopolysaccharide (LPS)-induced murine macrophage cells when treated with EA in a specific time. It was observed that LPS-stimulated TNF-α and interleukin-6 (IL-6) production were inhibited in treated cell lines. EA potentially inhibited LPS-induced production of PGE2, nitric oxide, and IL-6.[24] Topical application of isolated pomegranate EA had anti-inflammatory effects in ex vivo through the skin and was found to modulate cyclooxygenase-2 regulation in the viable epidermis. The method has potential in ameliorating the inflammation and pain-caused skin disorders.[25]

Antiulcerative activity

The antiulcerative activity of a hydroalcoholic extract of pomegranate flower and the EA-enriched fraction was found to be similar with the antiulcerative activity exhibited by sulfasalazine and sodium cromoglycate (standard drugs).[23]

Anticarcinogenic activity

EA was found to activate several signaling pathways of apoptosis, oxidative deoxyribonucleic acid damage prevention, or LDL-oxidation and alter growth factor expression. It interfered also with the nuclear factor kappa B, expression of p53, and peroxisome proliferator activated receptors family responsive genes.[26] It inhibited the formation and propagation of human umbilical vein endothelial cells (HUVEC) tube on an extracellular rebuilt matrix and revealed strong antiproliferative activity against the cell lines of colon, breast, and prostate cancer, where normal human lung fibroblast cells were taken as a normal cell line.[27] In the past decades, EA was reported to restrain the proliferation of different types of cancer cell lines as summarized in [Table 2].
Table 2: Antiproliferation effect of ellagic acid on different cell lines

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Antioxidant activity

Formation of ROS can give rise to oxidative stress, which may cause cell damage that leads to cell death. Therefore, cells have antioxidant networks to scavenge excessively produced ROS.[37] In ferric thiocyanate method, 58.5% of scavenging activity was found for EA at 45 μg/mL concentration. 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity of EA (30 μg/mL) was found to be 85.6%. EA had also chelating effect on ferrous ions (Fe2+). At 45 μg/mL concentration of EA, it exhibited 48.9% chelation effect on ferrous ions. On the other hand, chelating capacity of ferrous ions is 96.2% for ethylenediaminetetraacetic acid, 68.1% for butylated hydroxyl anisole, 64.5% for butylated hydroxytoluene, 81.2% for α-tocopherol, and 72.3% for ascorbic acid with the same concentration of EA. At 45 μg/mL concentration of EA, hydrogen peroxide scavenging activity was found to be 51.6%.[38]

Cardioprotection activities

EA at 200 mg/kg concentration had a significant cardioprotective effect in doxorubicin-induced cardiotoxicity. Oral treatment of EA (at 200 mg/kg) produced a significant reduction in the level of serum creatine kinase and lactate dehydrogenase when compared to doxorubicin group. The oral pretreatment with EA at same concentration revealed a significant reduction in QT interval and ST-segment along with nonsignificant decrease in QRS complex when compared to doxorubicin-treated rats.[39] EA was administered in hypertensive rats and blood pressure was recorded by tail-cuff plethysmography. Hypertension was reduced by treatment with EA (10 or 30 mg/kg). The blood levels of nitrate/nitrite were reduced in hypertensive rats and EA restored these levels. EA attenuated hypertension, possibly improving nitric oxide bioavailability.[40]

Antidiabetic activity

In recent modern medicinal therapy, there is no satisfactory treatment to cure diabetes mellitus. The demand for natural product possessing antidiabetic property is increasing day by day in our society because of less side effects and suitable pharmacological activity.[41] EA was found to decrease the glucose level significantly. It is also found to increase the plasma insulin level and C-peptide level through the action on β-cells of the pancreas.[42]

Antimicrobial activity

EA had significant antimicrobial properties against both Gram-positive and Gram-negative bacteria. Less than 10 parts per million (ppm) concentration of EA provided potential antibacterial activity against Bacillus subtilis, Bacillus cereus, and Bacillus polymyxa after 60 h of incubation. EA also exerted significant anti-bacterial activity against Escherichia coli after 60 h of incubation, and the minimum inhibitory concentration (MIC) was 20 ppm. For species of Salmonella, Salmonella paratyphi, Salmonella choleraesuis, and Salmonella enteritidis treated with EA for 60 h in a suitable condition, MIC was found to be 20 ppm for S. paratyphi, 10 ppm for S. choleraesuis, and 15 ppm for S. enteritidis.[43]

Due to thermal instability, strictinin as a bioactive chemical of the ET family obtained from tea infusion was completely decomposed to EA after being autoclaved and was evaluated for antiviral activity against influenza virus A/Puerto Rico/8/34. A plaque reduction assay was employed to estimate the relative inhibitory potency of EA against human influenza virus A. EA (at 50 μM concentration) inhibited more than 50% of plaque formation.[44] EA exerted potentialin vitro anti-human immunodeficiency virus (HIV)-1 activity in enzyme inhibition assays carried out against HIV-1 integrase and HIV-1 protease enzymes, respectively.[45] It was found to be active against fungal strains of Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton violaceum, Trichophyton schoenleinii, Trichophyton verrucosum, Microsporum canis, Candida albicans, and Candida tropicalis.[46]

Antidepressant activity

EA significantly decreased immobility periods of unstressed and stressed mice at 17.5 and 35 mg/kg orally. It also decreased the plasma nitrite levels in stressed mice and showed antidepressant-like activity in unstressed mice probably by interacting through adrenergic and serotonergic systems. Antidepressant-like activity of EA might be due to the inhibition of induced nitric oxide synthase.[47]

When EA was administered acutely or chronically, it produced a significant reduction in the duration of immobility mediated through an interaction with the monoaminergic system (serotonergic and noradrenergic systems), but EA had no effect on the locomotors activity.[48] It can be used as an effective herbal treatment to prevent cholinergic dysfunctions and oxidative stress associated with Alzheimer's type dementia.[49]

Antiatherogenic effects

A condition in which plaque builds up inside arteries is known as atherosclerosis or hardening of arteries. Plaque is made up of lipids, cellular waste products, calcium, fibrin, and fatty substances. Metabolites of EA such as urolithin A, B, C, and D exerted antiatherogenic effects. Urolithins and EA were able to lessen the discharge of cellular bond molecule and pro-inflammatory cytokine (IL-6) and the linkage of THP-1 monocytes to HUVECs. Urolithin A and urolithin B at 10 μM concentration reduced cholesterol accumulation significantly.[50]

Inhibition of cytochrome P450 (CYP450) and food-drug interaction

Cytochrome P450 (CYP450) mainly processed and biosynthesized multiple of endogenous substrate and exogenous xenobiotics. The transformation of the inactive prodrug to the pharmacologically active metabolites in the human body was through heme-containing monooxygenases. On the binding site, CYP isozymes were interacted by both CYP inducers and inhibitors and interfere with CYP substrates. CYP inhibitors intensify other medicines' toxicity profile that was accumulated in the body. From the body, drugs were eliminated through CYP inducers, and the activity was much diminished.[51]

The inhibition of CYP450 enzymes by the bioactive molecules of dietary supplements or herbal products may lead to greater potential for the toxicity of coadministered drugs. EA has a low probability of food-drug interaction in comparison to quercetin and gallic acid. The conclusion was drawn based on the inhibition of CYP3A4 and CYP2D6 with fluorometric high-throughput screening.[52]


  Conclusion Top


Naturally, available EA plays a significant role in food science as a dietary polyphenol has a multidimensional impact on human health. EA has anti-inflammatory activity and potentially inhibited LPS-induced PGE2 synthesis. It was also found to inhibit the production of nitric oxide and IL-6. EA is also a significant DPPH free-radical scavenger. EA-induced apoptosis in cancer cells and interacted with cancer-induced molecules. It is also a cardioprotective and antidiabetic agent as it decreased the blood glucose level and increased insulin sensitivity. EA is an antimicrobial agent and active against both Gram-positive and Gram-negative bacteria. It is also a potent inhibitor of HIV-1 integrase and HIV-1 protease. EA is active against fungal strains too. EA has shown antidepressant-like activity, and dietary intake of EA may prevent atherosclerosis. Biodynamic activities of EA already reported in the literature suggest that EA may be a potential candidate for pharmaceutical drug discovery. It also may be useful for the formulation of dietary supplements. Further clinical research is needed to make a formulation containing EA with validated biological response. Therefore, it can be concluded that research on EA may unravel a new direction for natural product researchers and lead to new findings in the prevention of chronic degenerative diseases.

Acknowledgments

The authors are grateful for the E-resources provided by the Tripura University (A Central University), Suryamaninagar, Agartala - 799 022, Tripura, India. We are also grateful to the University Grant Commission, Government of India, for providing Startup Grant (F. 20-2 (24)/2012 [BSR]) for newly recruited faculty and as financial support. We are also acknowledging the Department of Science and Technology (DST), Government of India, for awarding DST Fast Track Scheme (NO. SB/FT/CS-150/2012). The authors are also indebted to Dr. Partha Sarathi Gupta, Assistant Professor, Department of English, Tripura University (A Central University), Suryamaninagar, Agartala - 799 022, Tripura, India, and Smt. Rama Chowdhury, Assistant Professor, Department of English, BIR Bikram Memorial College, College Tilla, Agartala - 799 004, West Tripura, India, for English editing of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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