Sreejith P S et al. / Journal of Pharmacy Research 2012,5(5),2723-2728 Review Article Available online through ISSN: 0974-6943 http://jprsolutions.info A review on the pharmacology and phytochemistry of traditional medicinal , (Retz.) Correa

Sreejith P S, Praseeja R J, Asha V V* Plant Based Bioactives and Disease Biology Laboratory,Rajiv Gandhi Centre for Biotechnology,Thiruvananthapuram, India. Received on:14-02-2012; Revised on: 16-02-2012; Accepted on:21-04-2012

ABSTRACT Glycosmis pentaphylla (Retz.) Correa belongs to family. It is commonly known as Orange (English). G. pentaphylla has a long history of usage in traditional medicine against various ailments around the world. In Ayurvedic and other traditional medicinal practices the plant has been used against diseases like bilious complaints, cough, worms, jaundice, fever, inflammation, rheumatism, anaemia and vermifuge. Phytochemicals like alkaloids, flavonoids, terpenes and sterols have been isolated. Important pharmacological activities such as hepatoprotective, anti-inflammatory, anti-tumour, antioxidant, antibacterial, anti-viral, anti-ulcer, chemo protective and antiseptic properties were shown by researchers. This review presents a detailed survey of the literature on various traditional uses, phytochemicals and pharmacological properties of G. pentaphylla.

Keywords: Glycosmis pentaphylla, traditional uses, phytochemicals, pharmacological activities.

INTRODUCTION The herbal drugs have gained importance in the last few decades and their In parts of Asia the orange berry leaf is boiled down and used to reduce fever, prevalence is continuously increasing in both developing and developed coun- liver complications and various intestinal parasites. The traditional healers in tries. Herbal drug are considered to be safer with lesser side effects. This is Gazipur district of Bangladesh utilize G. pentaphylla for prevention of all the most important factor for the wide acceptance of herbal medicine through- forms of cancer [7]. Stem and fruits of G. pentaphylla is used by medicinal out the world. Plant based natural products have been the source of most of practitioners in Bangladesh for the treatment of rheumatoid arthritis [9]. the medicines or ingredients of medicines. It has been reported that more than 80% of drug substances were natural products or their development was Roots were used in India against facial inflammation, rheumatism, jaundice inspired by natural compounds [1]. The currently available technological and anaemia [10].The root, stem and leaf of this plant are used in folklore advances and interdisciplinary research approach have speeded up the isola- medicine in Kerala and Tamil Nadu to cure fever, rheumatism etc [11]. Leaf tion and characterisation of pharmacologically important molecules from juice is given with sugar in empty stomach in the morning to eradicate ascaris. natural sources. The traditional folk medicines of India use medicinal plant [12]. Crushed root piece mixed in water is administered in empty stomach in based drugs for preventing or suppressing various diseases [2]. the morning to cure stomach pain. Juice of leaves is used in fever and liver complaints and as a vermifuge. Roots pounded and mixed with sugar are G. pentaphylla is a common traditional/folklore medicinal plant used around given in low fever and the wood of this plant has also traditionally been used the world against various ailments. Recent scientific publications support to treat snakebite or to aid in appetite encouragement for women after childbirth this traditional use. The plant is native to eastern, southern, and south- [14]. eastern Asia and north-eastern Australia. G. pentaphylla is widely distributed from India, Malaysia and Southern China to the Philippine Islands where it In addition to these internal uses, orange berry has been utilized to help with occurs in tropical forests at low altitudes [3]. This plant is a small or medium excessive skin dryness. Folk medicinal practitioner in Jessore District, sized evergreen or small without thorns. It normally grows up to Bangladesh uses G. pentaphylla in combination with other to prevent 4 m tall. The review will provide an outline of currently published research bleeding from external wound as well as treatment of bone fracture and frac- articles on the pharmacology and phytochemistry of G. pentaphylla. ture induced pain [8]. Paste of leaves with ginger is used in eczema and skin affections. Leaves are considered as good antidote for eczema and other skin Traditional Uses troubles and applied in the form of paste [13]. Ayurveda, a traditional treatment system in India, have mentioned about the usage of this plant against various ailments. But a conventional scientific Stem used as toothbrushes for its fibrous nature and slightly astringent and background to support this traditional knowledge is limited. The plant is bitter quality. The fruits are edible and appreciated in some parts of the used for cough, rheumatism, anaemia and jaundice [4-6]. Stems and roots of world. Besides, leaves of this plant are used to keep insects away from plant are used for treatment of ulcer. Paste of leaves, with a bit of ginger, sweets and other edible items by natives in India, South Africa and Australia applied over the navel for worms and other bowel disorders. [15]. G. pentaphylla have been reported as indigenous bio-pesticides that continued to be in use by the farmers of Kerala [16].

*Corresponding author. Chemical Constituents Dr.V.V Asha Recently a number of reports regarding the phytochemical analysis of G. Plant Based Bioactives and Disease Biology Laboratory pentaphylla have been published. Some of the major classes of compounds Rajiv Gandhi Centre for Biotechnology reported from G. pentaphylla include terpenoids [17], amides [18-24], imides Thiruvananthapuram, India. [25], alkaloids [26-28], coumarins [29] and flavonoids [30]. Phytochemicals

Journal of Pharmacy Research Vol.5 Issue 5.May 2012 2723-2728 Sreejith P S et al. / Journal of Pharmacy Research 2012,5(5),2723-2728 such as arborinine, glycozolicine, 3- formyl carbazole, glycosinine, mupamine, hepatoprotective activity against CCl4 induced hepatotoxicity in rats [51]. varbazole, 3- methyl carbazole, glycolone, glycozolidol, glycozolinine, Recent work suggested that the methanol extracts of G. pentaphylla signifi- glycophymoline, glycophymine, glycomide, glycozoline, noracronycine, des- cantly decrease the levels of serum markers after treating with different N-methylacrocynine and des-N-methylnoracronycine have been reported concentration CCl4. The results are further supported by histopathological from this plant [31-40]. Air dried leaves yielded two furoquinoline bases, studies of liver tissue. Their results further confirmed that the methanol kokusaginine and skimmianine. Other alkaloids reported from the leaves extracts offer significant dose dependent protection against carbon tetra chlo- include glycosine, arborine, glycosminine, arborinine (major), glycosamine, ride (CCl4) induced hepatic injury [52]. glycorine, glycosmicine, g-fagarine triterpenes, arbinol and isoarbinol, The hepatoprotective effect of stem bark of G. pentaphylla against the CCl arborinone, two isomeric terpene alcohols, myricyl alcohol, stigmasterol and 4 ß-sitosterol. Roots contain the carbazole alkaloids, glycozolicine, 3- induced jaundice in rats has been reported early. The study showed that the rd th formylcarbazole, glycosinine, glycozoline, glycozolidine, skimmianine, ?- crude extracts were administered orally for 7 days. On the 3 and 6 day, the rats were given CCl and olive oil subcutaneously in 50:50 ratios. The blood fagarine and dictamine. Stems contain arborinine; other minor alkaloids also 4 th occur in this plant. The alkaloids arborine, arbornine, skimmianine, glycorine, samples were taken on the 8 day and serum liver enzymes such as alanine glycophymine, glycophymoline, glycosmicine and glycomide have been iso- transaminase (ALT), aspartate aminotransferase (AST), glutamyl lated from the flowers. Glycoric acid has been isolated from the methanolic transpeptidase (GGT) and total bilirubin were analysed. The results of the extract of the plant [41]. Six isoflavone glycosides like 3‘,7-dihydroxy-4‘,5,6- study showed the crude extract of G. pentaphylla demonstrated the ability to trimethoxyisoflavone 7-O-(5-O-trans-p-coumaroyl)-ß-d-apiofuranosyl- prevent hepatic injury/liver necrosis in the preventive group and showed (1>6)-ß-d-glucopyranoside, 2‘,7-dihydroxy-4‘,5‘,5,6-tetramethoxyisoflavone enhanced regeneration on the curative group [53]. 7-O-(5-O-trans-p-coumaroyl)-ß-d-apiofuranosyl-(1>6)-ß-d-glucopyrano- side, 2‘,7-dihydroxy-4‘,5‘,5,6-tetramethoxyisoflavone 7-O-ß-d- The hepatoprotective efficacy of the butanol extract obtained from the aerial apiofuranosyl-(1>6)-ß-d-glucopyranoside,7-hydroxy-4‘,8- parts of G. arborea has been reported. Albino rats were prophylactically rd dimethoxyisoflavone 7-O-ß-d-apiofuranosyl-(1>6)-ß-d-gluco-pyranoside , treated with the extract for 3 weeks. At the end of 3 week all the groups 7-hydroxy-4‘,6-dimethoxyisoflavone 7-O-ß-d-apiofuranosyl-(1>6)-ß-d- were injected with hepatotoxic agents. After 48 h of injection liver function glucopyranoside , and 4‘,5-dihydroxy-3‘,7-dimethoxyisoflavone 4‘-O-ß-d- tests and histopathological studies were performed. They found that the G. apiofuranosyl-(1>6)-ß-d-gluco-pyranoside have been reported [42-47]. arborea extract was able to overcome the toxic effects of hepatotoxic agents Hydroquinone diglycoside acyl esters like, glypentosides and seguinoside, in terms of lowering the levels of serum glutamate pyruvate transaminase Glypentosides as methoxyquinol 4-O-[(5-O-trans-p-coumaroyl)-ß-D- (GPT), alkaline phosphatase (ALP) and increased level of super oxide apiofuranosyl-(1 > 2)-ß-D-glucopyranoside] and 4-demethylantiarol 4-O- dismutase (SOD) in serum. Thiobarbituric acid reactive substances (TBARS) [(3-methoxy-4-hydroxy-benzoyl)-ß-D-apiofuranosyl-(1 > 2)-ß-D- generation in liver was also altered. Moreover, necrosis of liver produced by CCl was reversed by the extract. All these results showed the glucopyranoside were reported from the stem of G. pentaphylla [48]. 4 hepatoprotective activity of butanol extract of G. arborea [54].

Pharmacological Properties The hepatoprotective effect of leaf and stem bark extract of G. pentaphylla in Recent pharmacological studies support the traditional medicinal use of G. albino rats were described after inducing hepatic injury with CCl4 . Param- pentaphylla. Several biological activities of G. pentaphylla have been reported. eters studied were includes plasma ALT, AST, ALP, total bilirubin and tissue The major findings are given below. histopathology. Recovery of hepatic tissue was indicated with the highest dose (750 mg/kg body wt.) of leaf extract. The therapeutic dose range was Anti- hepatocellular carcinoma (HCC) activity devoid of toxic effects. Toxicity of leaf extract was observed histopathologi- Recent study has showed that the alcohol extract of G. pentaphylla induces cally and it was above 2.5 g/kg body weight [55]. apoptosis on the hepatocellular carcinoma cell line (Hep3 B). The study has identified the major pharmacologically active molecule as is flavonoid which Antibacterial activity induces apoptosis by increasing the ratio of expression of apoptotic regula- The anti-bacterial effect of different solvent extracts of stem and leaves of G. tor Bax and Bcl2 in a time and dose dependent manner [49]. pentaphylla was described recently. The activities of the extracts were not significantly enough against most of the tested organisms. Chloroform ex- Hepatoprotective activity tracts showed relatively better antimicrobial effect against the tested organ- Hepatoprotective activity of G. pentaphylla against paracetamol induced isms. Whereas petroleum ether extracts were inactive against most of the hepatic damage in Swiss albino mice has reported recently. The biochemical tested organisms. Chloroform and methanol extracts of leaves exhibited higher observations were supported by histopathological examination of liver sec- activities against Staphylococcus aureus. This study may be a lead for fur- tions from different experimental groups. The study has validated the ther ethnopharmacognostic investigation to identify new compounds with hepatoprotective efficacy of methanol and petroleum ether extracts of G. therapeutic promise [56]. pentaphylla. The results suggest that methanol extract of G. pentaphylla have higher hepatoprotective activity against paracetamol induced hepatotoxicity Recently it has proved that the anti-bacterial activity of methanolic extracts [50]. of leaves and stems of G. pentaphylla against 12 test bacteria. The methanolic extracts of leaves and stems were found to inhibit the growth of several microbial in agar media. Several bacteria were found to be insensitive Wistar rats were treated with different concentrations of CCl4 and proved the hepatoprotective effect of methanolic extracts of G. pentaphylla. The to the extracts. However, the methanolic extract of stems showed significant hepatoprotective effect of the extract was further confirmed by the histo- antimicrobial activity against Escherichia coli and Salmonella paratyphi. The pathological examinations of the liver sections which revealed that the nor- antimicrobial activity could justify its traditional use as toothbrush [57]. mal liver shape was disturbed by hepatotoxins intoxication and that was normalised after the extract treatment. It was concluded from the The antimicrobial activity of leaf, stem and root extracts of G. pentaphylla study that ethyl acetate and methanolic extracts of G. pentaphylla possess were evaluated with different solvent extracts viz., petroleum ether, metha

Journal of Pharmacy Research Vol.5 Issue 5.May 2012 2723-2728 Sreejith P S et al. / Journal of Pharmacy Research 2012,5(5),2723-2728 nol and acetone. Bacteria like Bacillus subtilis and E. coli were used for study. scavenging activity and have hepatoprotective action also. The overall anti- The results of the study revealed that the methanolic extract of all parts of oxidant and hepatoprotective activity of extract might be attributed to its the plant showed effective antimicrobial activity against the tested organ- triterpenoids and polyphenolic content and other phytochemical constitu- isms. However, the methanolic extract of stem part of this plant showed ents. The findings of the study suggested that G. pentaphylla could be a highest activity against the bacterium, Bacillus subtilis. Antibacterial effect potential natural source of antioxidants and could have greater importance as of alkaloid especially graveoline and arborine from G. pentaphylla against therapeutic agent [60]. Gram negative bacteria and its synergistic combination with suitable anti- bacterial chemotherapeutics also have reported [58]. Antipyretic activity In recent a number of researchers have reported the antipyretic activity of G. The antibacterial activity of G. pentaphylla was estimated by disc diffusion pentaphylla in in vivo rat models. The study revealed that ethanolic extracts method. The studies have evaluated different solvent extracts against a num- of G. pentaphylla have good antipyretic activity in Brewer’s yeast induced ber of gram positive and negative microbes. It was identified that the metha- pyrexia in rats. In general, non-steroidal anti-inflammatory drugs produce nol extract of G. pentaphylla exhibits a lower antibacterial activity against their antipyretic action through the inhibition of prostaglandin synthetase Staphylococcus aureus, Streptococcus beta haemolyticus, Bacillus cerus, B. within the hypothalamus. Therefore, the antipyretic activity of G. pentaphylla proteus, Shigella sonnei, S. siga, Pseudomonas aeruginosa, Klebsiella sp. is probably by inhibition of prostaglandin synthesis in hypothalamus [61, The high degree of antimicrobial activity seems to support the folk therapy 62]. for infectious and traditional therapeutic claims of this plant [52]. Anti-tumor activity Antifungal activity Brine shrimp lethality bioassay technique was applied for the determination Compounds exhibiting antifungal activities have isolated and reported from of general toxic property of the stems and leaves extracts of G. pentaphylla. several Glycosmis species [66, 67]. Recent findings evaluated the antifungal The in vitro lethality test has been carried out using brine shrimp nauplii eggs activity of chloroform, petroleum ether and methanol extracts from stem of i.e. Artemia salina. The results suggested that the methanolic extracts pre- G. pentaphylla against different fungal . Petroleum ether extract did not pared from stem of G. pentaphylla exhibits cytotoxic activity. Their findings show any inhibitory effect against tested fungus. The fungus Aspergillus clearly indicate the presence of potent anticancer bioactive principles in niger showed resistant against all the crude extracts. Of the three extracts, these extracts. Further studies regarding their isolation and characterisation only chloroform and methanol extract was found to be active against all the are a need for tomorrow. This might be very useful as anti-proliferative, tested fungi like Aspergillus flavus, Mucor sp and Candida sp [58]. antitumor and other bioactive agents in future [57, 60].

Anthelmintic activity The potential chemopreventive role of the hydro alcoholic leaf extract of G. Helminthic infections are now being recognized as cause of much chronic ill pentaphylla was evaluated. The study found that specific activities of Cytb5, health and sluggishness amongst the tropical people. More than half of the glutathione S-transferase (GST), Glutathione (GSH), Glutathione peroxidase population in the world suffers from worm infection of one or the other. The (GPx), Glutathione reductase (GR), and SOD were significantly enhanced traditional knowledge related to anthelminthic activity of extract is well dose dependently by the extracts. The activity of CytP450 was observed to known. The recent study showed that G. pentaphylla roots showed potent be increased only in the groups treated with a high dose of the extract. The anthelmintic activity on the earthworm, Pheretima posthumous. The study findings indicate that the chemopreventive role of G. pentaphylla extract is demonstrated that the methanol extract have greater activity than other ex- through the synthesis of carcinogen metabolizing enzymes [63]. tracts [65]. The antitumor activity of G. pentaphylla was recently attributed by many Antioxidant activity researchers. The results showed a potent inhibition of tumor produced by Recently scientist has performed a survey of the antioxidant effect of differ- Agrobacterium tumefaciens on potato disc. Potato disc bioassay is a simple, ent solvent extracts of G. pentaphylla by using 1, 1-diphenyl-2-picrylhydrazyl convenient and inexpensive method for bioassay guided fractionation and (DPPH) method. The results found that the methanolic extract of G. isolation of active antitumor compounds. The final results Arborinine, an pentaphylla stem showed moderate antioxidant property whereas the leaf acridone alkaloid obtained from G. pentaphylla, exhibited significant inhibi- extract showed very little activity. This antioxidant activity may be due to tion of crown gall tumors produced by Agrobacterium tumefaciens in a some polyphenolic compounds identified from this plant. The study results potato disc bioassay [64]. also indicated that G. pentaphylla contain a good source of medicinally im- portant molecules [57]. Wound healing activity Current findings suggest that the wound healing property shown by G. Latest study has investigated the antioxidant effect of the ethanolic leaf arborea syn. G. pentaphylla (Retz.) Correa (Rutaceae) is partly due to the extracts of G. pentaphylla. The antioxidant activity was evaluated by various increase in collagen synthesis, probably due to the presence of a mixture of antioxidant assays, including DPPH, 2, 2’-azino-bis (3-ethylbenzthiazoline- phytoconstituents in the plant. The preliminary phytochemical screening of

6-sulfonic acid) (ABTS), nitric oxide and hydrogen peroxide (H2O2) scaveng- G. arborea leaf extract showed the presence of flavonoids, triterpenoids, ing method. The antioxidant activities of extracts were compared with stan- alkaloids and polyphenols. Thus from this preliminary study it has estab- dard ascorbic acid. The findings suggested that this plant could be a potential lished that the G. arborea leaf extract has a reproducible wound healing natural source of antioxidants and could have greater importance as therapeu- potential and hereby justifies its use for wound healing in folklore medicine tic agent in preventing or slowing oxidative stress related degenerative dis- in India [78]. eases. The overall antioxidant activity of these extracts might be attributed to its flavonoids, phenolic and other phytochemical constituents [59]. Anti-inflammatory activity The anti-inflammatory effect of methanolic and ethyl acetate extracts of The antioxidant study with different crude extracts (petroleum ether, ethanolic roots of G. pentaphylla in carrageenan induced paw oedema in albino Wistar and aqueous) of G. pentaphylla showed that extracts exhibits free radical rats has already reported. The results show that the ethyl acetate extract

Journal of Pharmacy Research Vol.5 Issue 5.May 2012 2723-2728 Sreejith P S et al. / Journal of Pharmacy Research 2012,5(5),2723-2728 showing significant activity in reducing rat paw oedema [79].The activity of Rajiv Gandhi Centre for Biotechnology for their encouragement and sup- extract may due to the presence of Undecan-X. Recently a group of research- port. Authors are also thankful to Dr. A. Subramoniam former director TBGRI ers has isolated Undecan-2 from G. pentaphylla. Undecan-X-ones are a well- for his critical suggestions. The University Grand Commission and Depart- known anti-inflammatory compound [80, 81]. ment of Biotechnology, Govt. of India is also acknowledged for providing Research Fellowship to Sreejith P.S. and Praseeja R.J Insecticidal and larvicidal activity The larvicidal effect of G. pentaphylla have measured with larvae of Diaprepes REFERENCES abbreviatus L. (Coleoptera: Curculionidae) after rearing them on roots of 1. Sneader W. 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Some common plants used by kurichiar tribes of tirunelli forest, Wayanad CONCLUSION district, Kerala in medicine and other traditional uses. Indian J The medicinal properties of G. pentaphylla is available both in the written Tradit Knowl. 07: 2008; 250-255. and non-written format as traditional knowledge since time immemorial. In 12. Ambasta SP. The useful plants of India. Published by National traditional medicines the plant has been used as treatment option against Institute of Science and Communication. New Delhi: 4th edition: cancer, inflammation, jaundice, fever, helminthic infection etc. Traditional 2000; 380-381. knowledge regarding the usage of this plant is many but the scientific re- 13. Chopra RN, Nayar SI, Chopra IC. Glossary of Indian medicinal search available today to support this knowledge is limited. Here we have plants. Published by CSIR, New Delhi: 204: 1956; p330. tried to compile all the available information from both traditional and pub- 14. Chopra RN, Nayar SL, Chopra IC. Supplement to the glossary of lished scientific literatures regarding the medicinal uses of G. pentaphylla. It Indian medicinal plants. CSIR, New Delhi: 1969; p27. will helpful for the future researchers to get the information in a nut shell. 15. Bonny BP, Paulose S, Sijesh CA. Validity of bio pesticides use This will provide tremendous opportunities for planning and conduct re- among farmers. J. Entomol. Res. 29: 2005; 197-199. search related to various aspects of this medicinal plant. 16. Namita A, Ranawat MS, Pankaj A, Zaman K. Pharmacognostic Acknowledgements and Preliminary phytochemical studies on the leaves of Glycosmis The authors express their gratitude to Dr. M. Radhakrishna Pillai director pentaphylla (Retz.) Corr. J. pharm. Res. 4: 2011; 1800-1801.

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