Research Article |
Corresponding author: Muhamad Insanu ( insanu@fa.itb.ac.id ) Academic editor: Plamen Peikov
© 2022 Husnunnisa Husnunnisa, Rika Hartati, Rachmat Mauludin, Muhamad Insanu.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Husnunnisa H, Hartati R, Mauludin R, Insanu M (2022) A review of the Phyllanthus genus plants: Their phytochemistry, traditional uses, and potential inhibition of xanthine oxidase. Pharmacia 69(3): 681-687. https://doi.org/10.3897/pharmacia.69.e87013
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Hyperuricemia is a risk factor for gout and other cardiovascular diseases. One of the therapies used is Allopurinol. Unfortunately, it has unwanted side effects. These conditions made researchers continue to seek and develop alternative treatments from natural products. One of which is from plants of the Phyllanthus genus. One of their contents was polyphenols, especially flavonoids. It is an alternative treatment for hyperuricemia because of its minimal side effects. The flavonoids in this genus were reported to have xanthine oxidase inhibitory: quercetin, kaempferol, rutin, apigenin, luteolin, myricetin, catechin, epicatechin, and epigallocatechin with IC50 values from 0.44 M to > 100μM. The presence of π-π interactions between planar rings A and C on flavones with phe 1009 and phe 914 and the addition of hydroxyl groups on flavonoid compounds plays a crucial role in inhibiting xanthine oxidase.
flavonoids, hyperuricemia, IC 50Phyllanthus, xanthine oxidase
The genus Phyllanthus is a plant group of the Phyllanthaceae family that consists of 1,301 species and is distributed widely in tropical and subtropical areas of Asia, Africa, America, and Australia (
Increased activity of one of the prominent pro-oxidant enzymes: xanthine oxidase (XO), is involved in the pathogenesis of several diseases such as gout, inflammation, heart failure, stroke, atherosclerosis, diabetes, hypertension, colitis, inflammatory bowel disease, and rheumatoid arthritis. XO inhibition is the most widely accepted and effective treatment strategy for gout, hyperuricemia, and associated renal dysfunction (
This plant of the Phyllanthus genus contains alkaloids and terpenoids, polyphenolic compounds such as flavonoids, phenolic acids, stilbenes, anthocyanins, coumarins, and lignins (
The present review article will summarize and provide a comprehensive update on the last 10th years regarding the xanthine oxidase inhibitory activity of polyphenolic compounds in plants of the Phyllanthus genus. This review covers the literature from the previous 10th years using the keywords: Phyllanthus, traditional use, ethnobotany, ethnopharmacology, pharmacology, chemical compounds, flavonoids, inflammation, antioxidants, and xanthine oxidase inhibitory activity in searches using the Google Scholar database, Science Direct, Pubmed, Springerlink and Scopus.
In Asia, Phyllanthus emblica L. (P. emblica) has been used as a medicinal plant to treat diseases. The fruit of Phyllanthus emblica Linn or Emblica officinalis Gaertn (Phyllanthaceae), commonly known as Indian gooseberry or Amla, is used in indigenous traditional medicine systems, including Ayurveda, to treat several ailments: colds, hay fever, cough, asthma, bronchitis, diabetes, cephalalgia, ophthalmopathy, dyspepsia, colic, flatulence, hyperacidity, peptic ulcer, erysipelas, skin disease, leprosy, hematogenesis, inflammation, anemia, emaciation, hepatopathy, jaundice, diarrhea, dysentery, bleeding, vaginal discharge, menorrhagia, heart disorders, and hair loss premature graying (
Traditionally, Phyllanthus niruri is used as an antiurolithiasis, antidiabetic, and antihyperuricemic agent (
Plants of the Phyllanthus genus contain metabolites in the form of alkaloids, terpenoids, and polyphenolic compounds such as flavonoids, phenolic acids, stilbenes, anthocyanins, coumarins, and lignins which can be seen in Table
No. | Species | Chemical Compound | Pharmacological Activity | References |
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1. | P. acidus | Quercetin 3′ -O-glucoside | Phyllanthus acidus was reported to have pharmacological activities: hepatoprotective and hypoglycemic in vivo, antioxidant, α-glucosidase inhibition, antinociceptive, antiinflammatory, and antimicrobial activity in-vitro. |
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Phyllanthin |
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Delphinidin-3-O-β-D-glucoside |
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Kaempferol-3-glucoside |
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Cyanidin 5-O-β-D-glucoside | ||||
Catechin-3′-methyl ether | ||||
Kaempferol-3-glucoside-7- rhamnoside | ||||
Epicatechin | ||||
Quercetin-3-O-rhamnoside (Quercitrin) | ||||
Kaempferol-3-rhamnoside-4′- xyloside | ||||
Quercetin | ||||
Kaempferol | ||||
Myricetin | ||||
Quercetin-3-6″-caffeylgalactoside | ||||
Quercetin-3-2″-p-coumarylglucoside | ||||
Myricetin-3-glucoside | ||||
Rutin | ||||
1. | P. acidus | Kaempferol-3,7-di-glucoside | ||
Quercetin-3-O-sulfate | ||||
Kaempferol-3-O-sulfate | ||||
2. | P. amarus | Quercetin 3′ -O-glucoside | Phyllanthus amarus showed antibacterial activity against Staphylococcus aureus (gram-positive) with a minimum inhibitory concentration (MIC) value of 17.7 µg/ml. |
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(2R,3S,4S)-leucodelphinidin |
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Delphinidin-3-O- β -D-glucoside | ||||
Kaempferol-3-glucoside | ||||
Cyanidin 5-O-β-D-glucoside | ||||
Ellagic Acid | ||||
3. | Phyllanthus debilis | Quercetin 3′ -O-glucoside | In vitro glochidon has moderate dose-dependent inhibitory activity against α-glucosidase, α-amylase, DPP-4, and PPAR-γ. The docking and MD results also showed that glochidon had moderate activity to inhibit DPP-4 and PPAR-γ, compared with standard agents and a strong tendency to interact with the GLUT1 protein. Computational ADME profiling determined that glochidon has excellent characteristics in acting as a hypoglycemic compound. In vivo, experimental results showed that at a dose of 20 mg/kg, glochidon significantly increased body weight, plasma insulin, HDL levels, and other biochemical markers. In addition, it lowers blood glucose, total cholesterol, triglycerides, low-density lipoprotein, and very-low-density lipoprotein. |
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Betulinic acid |
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Gallocatechin | ||||
(2R,3S,4S)-leucodelphinidin | ||||
Delphinidin-3-O- β -D-glucoside | ||||
4. | Phyllanthus emblica | Quercetin 3′ -O-glucoside | This plant provides various pharmacological activities: antioxidant, anticancer, immunomodulatory, anti-inflammatory, cell protection, diabetes management, dyslipidemia, obesity, cancer, liver disorders, arthritis, gingivitis, and wound healing. In addition, Phyllanthus emblica also has anti-aging activities, such as antioxidants, antityrosinase, and antimelanogenesis, and can repair kidney damage caused by cisplatin. |
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Phyllanthin |
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Delphinidin-3-O- β -D-glucoside |
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Kaempferol-3-glucoside |
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Cyanidin 5-O-β-D-glucoside |
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Quercetin | ||||
Rutin | ||||
Apigenin-7-O-(6’-butyryl-β- glucopyranoside) | ||||
Luteolin-4’-O-neohesperidoside | ||||
5. | Phyllanthus lawii | Quercetin 3′ -O-glucoside | Phyllanthus lawii has sturdily analgesic activity. This plant exerts significant peripheral and central analgesic activity in acetic acid-induced writhing mice. |
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Phyllanthin |
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Betulinic acid | ||||
Niranthin | ||||
Delphinidin-3-O- β -D-glucoside | ||||
Kaempferol-3-glucoside | ||||
Cyanidin 5-O-β-D-glucoside | ||||
Rutin | ||||
Hypophyllanthin | ||||
6. | Phyllanthus myrtifolius | Quercetin 3′ -O-glucoside | Phyllanthus myrtifolius inhibited the growth of Pseudomonas stutzeri (gram-negative) with a MIC value of 78 µg/ml. Intense inhibitory activity against HIV-RT with IC50 value = 12.7 µg/mL. Phyllanthus myrtifolius gave potent antioxidant activity against DPPH with IC50 value = 10.2 µg/mL. |
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Kaempferol-3-glucoside |
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Cyanidin 5-O-β-D-glucoside | ||||
Hypophyllanthin | ||||
7. | Phyllanthus reticulatous | Quercetin 3′ -O-glucoside | Phyllanthus reticulatous gave potent antioxidant activity to DPPH with IC50 value = 10.8 µg/mL. |
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Betulinic acid |
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Niranthin | ||||
Gallocatechin | ||||
(2R,3S,4S)-leucodelphinidin | ||||
Delphinidin-3-O- β -D-glucoside | ||||
Kaempferol-3-glucoside | ||||
Rutin | ||||
Ellagic Acid | ||||
Quercetin | ||||
8. | Phyllanthus urinaria | Quercetin 3′ -O-glucoside | Phyllanthus urinaria inhibited the growth of Pseudomonas stutzeri (gram-negative) bacteria with a MIC value of 117 µg/ml. Intense inhibitory activity against HIV-RT with IC50 value = 10.4 µg/mL. Phyllanthus urinaria gave potent antioxidant activity against DPPH with IC50 value = 17.4 µg/mL. |
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Phyllanthin |
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Betulinic acid | ||||
Delphinidin-3-O- β -D-glucoside | ||||
Ellagic Acid | ||||
Hypophyllanthin | ||||
9. | Phyllanthus virgatus | Quercetin 3′ -O-glucoside | The methanol extract of Phyllanthus virgatus showed intense antioxidant activity and protection against oxidative DNA damage. In addition, the methanol extract of Phyllanthus virgatus inhibited α-amylase (IC50 = 33.20 ± 0.556 μg/mL), noncompetitively, compared to acarbose (IC50 76, 88 ± 0.277 μg/mL), which is competitive inhibition. Moreover, this extract triggered glucose uptake activity in 3T3-L1 cells and showed a good correlation between antioxidant activity and α-amylase. Molecular docking studies of the main bioactive compounds (9,12-octadecadienoic acid, asarone, 11-octadecenoic acid, and acrylic) via GC-MS analysis of these extracts indicate that the inhibitory properties might be due to the synergistic effect of these bioactive compounds. |
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Betulinic acid |
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Zeatin | ||||
Delphinidin-3-O- β -D-glucoside | ||||
Kaempferol-3-glucoside | ||||
Rutin | ||||
Ellagic Acid | ||||
Hypophyllanthin | ||||
Quercetin | ||||
10. | Phyllanthus niruri | Quersetin 3-O-glukoside | This plant has bioactivity as antihyperuricemia, where the methanol extract of Phyllanthus niruri inhibits the xanthine oxidase enzyme with an IC50 value of 39.39 µg/mL. Phyllanthus niruri has antiinflammatory, antinociceptive, antiplasmodium, and antidiabetic pharmacological activity. |
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Catechin |
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Quersetin 3-O-α-rhamnoside |
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Epicatechin |
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Rutin |
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6-hydroxy-7,8,2’,3’,4’-pentamethoxyisoflavone |
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5,7-dimethoxy-3,4’-dihydroxy-3’,8-di-C-prenyl flavanonol |
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5,3’-dihydroxy-6,7,4’-trimethoxyflavone |
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7-hydroxy-2’,4’,5’-trimethoxyisoflavone | ||||
7-hydroxy-4’-methoxyisoflavone | ||||
11. | Phyllanthus orbicularis | Catechin | Fideloside is the main flavonoid that exerts antioxidant and antiinflammatory activity in human monocytes by showing an increased effect on the production of the antiinflammatory cytokine IL-10. The aqueous extract of Phyllanthus orbicularis used as a protector against DNA damage caused by exposure to sunlight (UV). Procyanidins B1 and B2 provided antiviral activity by inhibiting HSV-2 replication and DNA synthesis with EC(50) values = 32.8 µg/mL and 24.2 µg/mL, respectively. |
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Epicatechin |
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Procyanidin B2 |
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Rutoside |
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Nicotiflorin | ||||
Kaempferol | ||||
Procyanidin C1 | ||||
Fideloside | ||||
12. | Phyllanthus phillyreifolius | Rutin | Phyllanthus phillyreifolius extract has pharmacological activity as an anticancer, antiviral, antioxidant, and antibacterial. |
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Quercetin-3-glucuronide |
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Quercitrin |
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Lipoxygenases (LOX), cyclooxygenases (Coxs), and xanthine oxidase (XO) are metalloenzymes whose catalytic cycles involve ROS, such as lipid peroxyl radicals, superoxide, and hydrogen peroxide. LOX and Coxs will catalyze the prime steps of the leukotriene biosynthesis and prostaglandins from arachidonic acid. They are crucial cascades in the inflammatory response (
Flavonoids are a group of phenolic compounds with many properties, especially in counteracting free radicals in vitro and in vivo. Many studies have shown that flavonoids can inhibit the production of ROS enzymes, such as xanthine oxidase, nitric oxide synthase, and myeloperoxidase (
Inhibitory activity of xanthine oxidase from flavonoids of the Phyllanthus genus.
No. | Compound and Structure | IC50 value | Sources | References |
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1. | Quercetin | 0,44 – 2,92 µM | Phyllanthus acidus |
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Phyllanthus emblica |
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2. | Kaempferol | 0,67 – 2,5 µM | Phyllanthus acidus |
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Phyllanthus orbicularis |
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3. | Rutin | <50 µM | Phyllanthus acidus |
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Phyllanthus emblica | ||||
Phyllanthus niruri | ||||
Phyllanthus orbicularis | ||||
Phyllanthus phillyreifolius | ||||
4. | Myricetin | 1,27 - 2,38 µM | Phyllanthus acidus |
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5. | Apigenin | 0,44 – 1,0 µM | Phyllanthus emblica |
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6. | Luteolin | 0,55 – 2,38 µM | Phyllanthus emblica |
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7. | Cathechin | >100 µM | Phyllanthus fraternus |
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Phyllanthus niruri | ||||
Phyllanthus orbicularis | ||||
8. | Epicathechin | >100 µM | Phyllanthus acidus |
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Phyllanthus niruri |
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Phyllanthus orbicularis | ||||
9. | Epigalokatekin | >100 µM | Phyllanthus reticulatous |
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Planar rings A and C of flavones have π-π interactions with phe 1009 and phe 914, required for xanthine oxidase inhibition. However, the planar flavone framework alone is not sufficient to induce xanthine oxidase inhibition. A hydroxyl group at position 7 plays a role in the xanthine oxidase inhibition by flavones. The addition of the 5-hydroxyl group and the 7-hydroxyl decreased the IC50 value significantly. The structural similarity between 5,7-dihydroxyflavone (ring A) and enol xanthine indicates the same binding site in the allosteric center of xanthine oxidase (
The hydroxyl groups at positions C-5 and C-7 with the C2-C3 double bond play a key role in XO inhibitory activity. Flavones are slightly better XO inhibitors than flavonols, and all derivatives of flavonoids, except for isorhamnetin, are less active than the original compound (
The presence of a 2’-hydroxyl group can lower the inhibitory activity of xanthine oxidase, which can being see from the increase in the IC50 value of flavonoid compounds that have a 2’-hydroxyl group, for example, kaempferol (without 2’-hydroxyl group) compared to morin (the presence of a 2’-hydroxyl group), where the IC50 value increased from 2.5 to 40 µM, respectively. The presence of 3-hydroxyl can also attenuate the inhibition of xanthine oxidase, luteolin compared with quercetin (the presence of a 3-hydroxyl group) showed an increase in IC50 from 0.75 to 1.5 µM, respectively. The addition of the 8-hydroxyl group increased the IC50 value from 4 to 10 µM when 7.3’,4’-trihydroxyflavone compared with 7,8,3’,4’-tetrahydroxyflavone. The 5’-hydroxyl group doesn’t influence the inhibitory activity of xanthine oxidase (
The presence of hydroxyl groups at positions C-3 and C-3’ plays a role in superoxide scavenging activity (
Catechins have superoxide scavenging activity and do not interact with XO. Only flavonols with a catechol group in ring B (quercetin, myricetin, fisetin) showed additional superoxide activity. In contrast, some hydroxylated flavones (chrysin, apigenin, luteolin) exhibit underlying pro-oxidant activity. Interestingly, glycosidation of the flavonoid core generally abolishes XO inhibition. For example, the IC50 values of quercetin for XO inhibition and superoxide scavenging were 2.6 and 1.6 µM, respectively. Quercetin-3-O rhamnoside (quercitrin) had an IC50 of 8.1 µM to ward off superoxide but could not inhibit XO (IC50 > 100 µM). Similarly, Q3GlcU and Q7GlcU were very poor inhibitors of XO (Kd 100 µM). However, Q3’GlcU (Kd 1.4 µM) and Q4’GlcU (Kd 0.25 µM) exerted intense inhibition activity against XO, which was as strong as quercetin. Therefore, while glucuronidation at the 3’ or 4’ position suppresses the free catechol moiety of ring B and thus has radical scavenging activity, XO affinity has been spared as if flavonol-XO binding occurs with marginal participation of ring B (
Epicatechin and its oligomers have no inhibitory activity against XO. In contrast, an oligomer of epicatechin-3-O-gallate (4β-8 Interflavan linkage) are inhibitors whose potency increases with the number of monomer units (IC50 7.2 to 4.4 µM from dimer to tetramer). Thus, the French maritime pine bark extract (pycnogenol) rich in procyanidins (75% by weight, DP 2 to 7) find to significantly reduce XO activity and inhibit protein electrophoretic mobility only under non-denaturation. In addition, the pure low molecular weight extract components had no effect. Therefore, it concludes that XO inhibition occurs by binding to XO of high DP procyanidins (DP > 3) (
Nine flavonoids in the Phyllanthus genus are reported to have xanthine oxidase inhibitory activity. They were quercetin, kaempferol, rutin, apigenin, luteolin, myricetin, catechin, epicatechin, and epigallocatechin. Their IC50 was from 0.44 µM to > 100 μM. Quercetin and apigenin show the great activity of xanthine oxidase inhibitory compared to other flavonoids found in plants of the Phyllanthus genus with an IC50 value of 0.44 µM. The presence of – interactions between planar rings A and C on flavones with phe 1009 and phe 914, plays a chief role in inhibiting xanthine oxidase. Adding hydroxyl groups to flavonoid compounds can increase or decrease the inhibitory activity of xanthine oxidase. The hydroxyl groups at positions 5, 7, 3’, and 4’ can increase the inhibitory activity of xanthine oxidase, while the hydroxyl groups at 2’, 3, and 8 will decrease the inhibitory activity against xanthine oxidase.
The author would like to thank the Department of Pharmaceutical Biology, School of Pharmacy, Bandung Institute of Technology, for the facilities, and support that has been provided.