Oriental Pharmacy and Experimental Medicine

, Volume 19, Issue 4, pp 367–377 | Cite as

Protective and toxicogenetic aspects of Piper betle

  • Md. Matiur Rahman
  • A. T. M. Yusuf
  • Muhammad Torequl IslamEmail author


Piper betle L. (Paan) is used as a chewing material in many Asian and Oceanic countries. Piper betle extracts and its derivatives possess a number of important pharmacological activities, however, the toxicological reports on this plant is insufficient. This paper aims to discuss the protective and toxicogenetic effects of P. betle and its derived compounds on the basis of scientific reports found in the PubMed database. An up-to-date (Feb 2018) search made in the PubMed for scientific evidence suggests that P. betle and its derivatives have antioxidant, anti-inflammatory, anticancer, lipid-lowering, immuno-stimulatory, and organo-protective effects in various test systems. Safrole, hydroxy-chavicol, gamma-tocotrienol, hydroquinone, piperoleine A & B, allylpyrocatechol, and chavibetol are the important biologically active isolated components of various parts of P. betle. Safrole and hydroxy-chavicol are evident to exert both beneficial and toxic effects on the test systems. However, the toxicogenetic effects of the crude extracts of this herb and its compounds are dependent on the concentration/dose used. Of note, understanding toxicological impacts is crucial for any human consuming material. Piper betle is an important medicinal herb, however, more researches are necessary to claim its toxicogenetic effects.


Piper betle Toxicogenetics Protective effects 




Compliance with ethical standards

Ethical statement

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

Md. Matiur Rahman has no conflict of interest. A. T. M. Yusuf has no conflict of interest. Muhammad Torequl Islam has no conflict of interest.


  1. Abdul Rahman A, Jamal AR, Harun R, Mohd Mokhtar N, Wan Ngah WZ (2014) Gamma-tocotrienol and hydroxy-chavicol synergistically inhibits growth and induces apoptosis of human glioma cells. BMC Complement Altern Med 14:213PubMedPubMedCentralGoogle Scholar
  2. Amin SA, Bhattacharya P, Basak S, Gayen S, Nandy A, Saha A (2017) Pharmacoinformatics study of Piperolactam A from Piper betle root as new lead for non steroidal anti fertility drug development. Comput Biol Chem 67:213–224PubMedGoogle Scholar
  3. Arya DS, Arora S, Malik S, Nepal S, Kumari S, Ojha S (2010) Effect of Piper betle on cardiac function, marker enzymes, and oxidative stress in isoproterenol-induced cardiotoxicity in rats. Toxicol Mech Methods 20:564–571PubMedGoogle Scholar
  4. Atiya A, Sinha BN, Ranjan Lal U (2017) New chemical constituents from the Piper betle Linn. (Piperaceae). Nat Prod Res 32:1080–1087PubMedGoogle Scholar
  5. Bártíková H, Podlipná R, Skálová L (2016) Veterinary drugs in the environment and their toxicity to plants. Chemosphere 144:2290–2301PubMedGoogle Scholar
  6. Bhattacharya P, Mondal S, Basak S, Das P, Saha A, Bera T (2016) In Vitro susceptibilities of wild and drug resistant Leishmania donovani amastigotes to piperolactam A loaded hydroxypropyl-β-cyclodextrin nanoparticles. Acta Trop 158:97–106. CrossRefPubMedGoogle Scholar
  7. Byard RW, Musgrave I, Maker G, Bunce M (2017) What risks do herbal products pose to the Australian community? Med J Aust 206(2):86–90PubMedGoogle Scholar
  8. Calahan J, Howard D, Almalki AJ, Gupta MP, Calderón AI (2016) Chemical adulterants in herbal medicinal products: a review. Planta Med 82(6):505–515PubMedGoogle Scholar
  9. Chaimanee V, Thongtue U, Sornmai N, Songsri S, Pettis JS (2017) Antimicrobial activity of plant extracts against the honeybee pathogens, Paenibacillus larvae and Ascosphaera apis and their topical toxicity to Apis mellifera adults. J Appl Microbiol 123:1160–1167PubMedGoogle Scholar
  10. Chakraborty JB, Mahato SK, Joshi K, Shinde V, Rakshit S, Biswas N, Choudhury Mukherjee I, Mandal L, Ganguly D, Chowdhury AA, Chaudhuri J, Paul K, Pal BC, Vinayagam J, Pal C, Manna A, Jaisankar P, Chaudhuri U, Konar A, Roy S, Bandyopadhyay S (2012) Hydroxychavicol, a Piper betle leaf component, induces apoptosis of CML cells through mitochondrial reactive oxygen species-dependent JNK and endothelial nitric oxide synthase activation and overrides imatinib resistance. Cancer Sci 103:88–99PubMedGoogle Scholar
  11. Chang LY, Lin JC, Chang CW, Ho WH, Chen YT, Peng JL, Hung SL (2009) Inhibitory effects of safrole on phagocytosis, intracellular reactive oxygen species, and the activity of myeloperoxidase released by human polymorphonuclear leukocytes. J Periodontol 80:1330–1337PubMedGoogle Scholar
  12. Chang MC, Chen YJ, Chang HH, Chan CP, Yeh CY, Wang YL, Cheng RH, Hahn LJ, Jeng JH (2014) Areca nut components affect COX-2, cyclin B1/cdc25C and keratin expression, PGE2 production in keratinocyte is related to reactive oxygen species, CYP1A1, Src, EGFR and Ras signaling. PLoS ONE 9:e101959. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Chen HC, Chang YS, Lee TC (1984) The mutagenicity of nitrite-treated aqueous extract of Piper betle L. Proc Natl Sci Counc Repub China B 8:4–10PubMedGoogle Scholar
  14. Dash R, Emran TB, Paul A, Siddique MK, Khan MA, Rahman MG, Sarwar MS, Nasir Uddin MM (2016) Effects of five Bangladeshi Plant extracts on in vitro thrombolysis and cytotoxicity. Pharmacognosy Res 8:176–180PubMedPubMedCentralGoogle Scholar
  15. De S, Sen T, Chatterjee M (2015) Reduction of oxidative stress by an ethanolic extract of leaves of Piper betle (Paan) Linn. decreased methotrexate-induced toxicity. Mol Cell Biochem 409:191–197PubMedGoogle Scholar
  16. Durani LW, Khor SC, Tan JK, Chua KH, Mohd Yusof YA, Makpol S (2017) Piper betle L. modulates senescence-associated genes expression in replicative senescent human diploid fibroblasts. Biomed Res Int 2017:6894026. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Esa F, Ngah WZ, Jamal AR, Mohd Yusof YA (2013) Inhibition of beta-catenin and KRAS expressions by Piper betle in azoxymethane-induced colon cancer of male Fischer 344 rats. Anal Quant Cytopathol Histpathol 35:324–334PubMedGoogle Scholar
  18. Fan MJ, Lin SY, Yu CC, Tang NY, Ho HC, Chung HK, Yang JS, Huang YP, Ip SW, Chung JG (2012) Safrole-modulated immune response is mediated through enhancing the CD11b surface marker and stimulating the phagocytosis by macrophages in BALB/c mice. Hum Exp Toxicol 31:898–904PubMedGoogle Scholar
  19. Ganguly S, Mula S, Chattopadhyay S, Chatterjee M (2007) An ethanol extract of Piper betle Linn. mediates its anti-inflammatory activity via down-regulation of nitric oxide. J Pharm Pharmacol 59:711–718PubMedGoogle Scholar
  20. Gundala SR, Yang C, Mukkavilli R, Paranjpe R, Brahmbhatt M, Pannu V, Cheng A, Reid MD, Aneja R (2014) Hydroxychavicol, a betel leaf component, inhibits prostate cancer through ROS-driven DNA damage and apoptosis. Toxicol Appl Pharmacol 280:86–96PubMedPubMedCentralGoogle Scholar
  21. Huang XZ, Xu Y, Zhang YF, Zhang Y, Wong YH, Han Z, Yin Y, Qian PY (2014) Nontoxic piperamides and their synthetic analogues as novel antifouling reagents. Biofouling 30:473–481PubMedGoogle Scholar
  22. Ishtiaq S, Akram M, Kamran SH, Hanif U, Afridi MSK, Sajid-Ur-Rehman Afzal A, Asif A, Younus M, Akbar S (2017) Acute and sub-acute toxicity study of a Pakistani polyherbal formulation. BMC Complement Altern Med 17(1):387PubMedPubMedCentralGoogle Scholar
  23. Jeng JH, Kuo ML, Hahn LJ, Kuo MY (1994) Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro. J Dent Res 73:1043–1049PubMedGoogle Scholar
  24. Jeng JH, Hahn LJ, Lin BR, Hsieh CC, Chan CP, Chang MC (1999) Effects of areca nut, inflorescence Piper betle extracts and arecoline on cytotoxicity, total and unscheduled DNA synthesis in cultured gingival keratinocytes. J Oral Pathol Med 28:64–71PubMedGoogle Scholar
  25. Jeng JH, Wang YJ, Chang WH, Wu HL, Li CH, Uang BJ, Kang JJ, Lee JJ, Hahn LJ, Lin BR, Chang MC (2004) Reactive oxygen species are crucial for hydroxychavicol toxicity toward KB epithelial cells. Cell Mol Life Sci 61:83–96PubMedGoogle Scholar
  26. Kahaliw W, Hellman B, Engidawork E (2018) Genotoxicity study of Ethiopian medicinal plant extracts on HepG2 cells. BMC Complement Altern Med 18:45PubMedPubMedCentralGoogle Scholar
  27. Kristanc L, Kreft S (2016) European medicinal and edible plants associated with subacute and chronic toxicity part I: plants with carcinogenic, teratogenic and endocrine-disrupting effects. Food Chem Toxicol 92:150–164PubMedGoogle Scholar
  28. Lee-Chen SF, Chen CL, Ho LY, Hsu PC, Chang JT, Sun CM, Chi CW, Liu TY (1996) Role of oxidative DNA damage in hydroxychavicol-induced genotoxicity. Mutagenesis 11:519–523PubMedGoogle Scholar
  29. Liu HN, Liu TY, Chen CC, Lee DD, Chang YT (2011) Insights into the mechanism of Piper betle leaf-induced contact leukomelanosis using C57BL/6 mice as the animal model and tyrosinase assays. Australas J Dermatol 52:172–178PubMedGoogle Scholar
  30. Majumdar B, Ray Chaudhuri SG, Ray A, Bandyopadhyay SK (2003) Effect of ethanol extract of Piper betle Linn leaf on healing of NSAID-induced experimental ulcer—a novel role of free radical scavenging action. Indian J Exp Biol 41:311–315PubMedGoogle Scholar
  31. Merlin M, Pezzotti M, Avesani L (2017) Edible plants for oral delivery of biopharmaceuticals. Br J Clin Pharmacol 83(1):71–81PubMedGoogle Scholar
  32. Milton Prabu S, Muthumani M, Shagirtha K (2012) Protective effect of Piper betle leaf extract against cadmium-induced oxidative stress and hepatic dysfunction in rats. Saudi J Biol Sci 19:229–239PubMedPubMedCentralGoogle Scholar
  33. Misra P, Kumar A, Khare P, Gupta S, Kumar N, Dube A (2009) Pro-apoptotic effect of the landrace Bangla Mahoba of Piper betle on Leishmania donovani may be due to the high content of eugenol. J Med Microbiol 58:1058–1066PubMedGoogle Scholar
  34. Mula S, Banerjee D, Patro BS, Bhattacharya S, Barik A, Bandyopadhyay SK, Chattopadhyay S (2008) Inhibitory property of the Piper betel phenolics against photosensitization-induced biological damages. Bioorg Med Chem 16:2932–2938PubMedGoogle Scholar
  35. Ng PL, Rajab NF, Then SM, Mohd Yusof YA, Wan Ngah WZ, Pin KY, Looi ML (2014) Piper betle leaf extract enhances the cytotoxicity effect of 5-fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells. J Zhejiang Univ Sci B 15:692–700PubMedPubMedCentralGoogle Scholar
  36. Owen PL, Matainaho T, Sirois M, Johns T (2007) Endothelial cytoprotection from oxidized LDL by some crude Melanesian plant extracts is not related to their antioxidant capacity. J Biochem Mol Toxicol 21:231–242PubMedGoogle Scholar
  37. Panda P, Aiko V, Mehta A (2015) Effect of aqueous extracts of Mentha arvensis (mint) and Piper betle (betel) on growth and citrinin production from toxigenic Penicillium citrinum. J Food Sci Technol 52:3466–3474PubMedGoogle Scholar
  38. Pinela J, Carvalho AM, Ferreira ICFR (2017) Wild edible plants: nutritional and toxicological characteristics, retrieval strategies and importance for today’s society. Food Chem Toxicol 110:165–188PubMedGoogle Scholar
  39. Psotová J, Chlopcíková S, Grambal F, Simánek V, Ulrichová J (2002) Influence of silymarin and its flavonolignans on doxorubicin-iron induced lipid peroxidation in rat heart microsomes and mitochondria in comparison with quercetin. Phytother Res 16:S63–S67PubMedGoogle Scholar
  40. Pushpavalli G, Veeramani C, Pugalendi KV (2008) Influence of Piper betle on hepatic marker enzymes and tissue antioxidant status in D-galactosamine-induced hepatotoxic rats. J Basic Clin Physiol Pharmacol 9:131–150Google Scholar
  41. Pushpavalli G, Veeramani C, Pugalendi KV (2009) Effect of Piper betle on plasma antioxidant status and lipid profile against D-galactosamine-induced hepatitis in rats. Redox Rep 14:7–12PubMedGoogle Scholar
  42. Saravanan R, Prakasam A, Ramesh B, Pugalendi KV (2002) Influence of Piper betle on hepatic marker enzymes and tissue antioxidant status in ethanol-treated Wistar rats. J Med Food 5:197–204PubMedGoogle Scholar
  43. Saravanan R, Rajendra Prasad N, Pugalendi KV (2003) Effect of Piper betle leaf extract on alcoholic toxicity in the rat brain. J Med Food 6:261–265PubMedGoogle Scholar
  44. Sazwi NN, Nalina T, Abdul Rahim ZH (2013) Antioxidant and cytoprotective activities of Piper betle, Areca catechu, Uncaria gambir and betel quid with and without calcium hydroxide. BMC Complement Altern Med 13:351PubMedGoogle Scholar
  45. Sengupta A, Adhikary P, Basak BK, Chakrabarti K, Gangopadhyay P, Banerji J, Chatterjee A (2000) Pre-clinical toxicity evaluation of leaf-stalk extractive of Piper betle Linn. in rodents. Indian J Exp Biol 38:338–342PubMedGoogle Scholar
  46. Singh M, Shakya S, Soni VK, Dangi A, Kumar N, Bhattacharya SM (2009) The n-hexane and chloroform fractions of Piper betle L. trigger different arms of immune responses in BALB/c mice and exhibit antifilarial activity against human lymphatic filarid Brugia malayi. Int Immunopharmacol 9:716–728PubMedGoogle Scholar
  47. Song H, Wan Y, Xu YY (2015) Betel quid chewing without tobacco—a meta-analysis of carcinogenic and precarcinogenic effects. Asia Pac J Public Health 27:NP47–NP57PubMedGoogle Scholar
  48. Srikanta BM, Sathisha UV, Dharmesh SM (2010) Alterations of matrix metalloproteinases, gastric mucin and prostaglandin E(2) levels by pectic polysaccharide of swallow root (Decalepis hamiltonii) during ulcer healing. Biochimie 92:194–203PubMedGoogle Scholar
  49. Stich HF, Stich W (1982) Chromosome-damaging activity of saliva of betel nut and tobacco chewers. Cancer Lett 15:193–202PubMedGoogle Scholar
  50. Stich HF, Rosin MP, Brunnemann KD (1986) Oral lesions, genotoxicity and nitrosamines in betel quid chewers with no obvious increase in oral cancer risk. Cancer Lett 31:15–25PubMedGoogle Scholar
  51. Tang DW, Chang KW, Chi CW, Liu TY (2004) Hydroxychavicol modulates benzo[a]pyrene-induced genotoxicity through induction of dihydrodiol dehydrogenase. Toxicol Lett 152:235–243PubMedGoogle Scholar
  52. Valle DL Jr, Puzon JJ, Cabrera EC, Rivera WL (2016) Thin layer chromatography-bioautography and gas chromatography-mass spectrometry of antimicrobial leaf extracts from Philippine Piper betle L. against multidrug-resistant bacteria. Evid Based Complement Altern Med 2016:4976791Google Scholar
  53. Vasantha-Srinivasan P, Senthil-Nathan S, Ponsankar A, Thanigaivel A, Edwin ES, Selin-Rani S, Chellappandian M, Pradeepa V, Lija-Escaline J, Kalaivani K, Hunter WB, Duraipandiyan V, Al-Dhabi NA (2017) Comparative analysis of mosquito (Diptera: Culicidae: Aedes aegypti Liston) responses to the insecticide Temephos and plant derived essential oil derived from Piper betle L. Ecotoxicol Environ Saf 139:439–446PubMedGoogle Scholar
  54. Vasantha-Srinivasan P, Senthil-Nathan S, Ponsankar A, Thanigaivel A, Chellappandian M, Edwin ES, Selin-Rani S, Kalaivani K, Hunter WB, Duraipandiyan V, Al-Dhabi NA (2018a) Acute toxicity of chemical pesticides and plant-derived essential oil on the behavior and development of earthworms, Eudrilus eugeniae (Kinberg) and Eisenia fetida (Savigny). Environ Sci Pollut Res Int 25:10371–10382PubMedGoogle Scholar
  55. Vasantha-Srinivasan P, Thanigaivel A, Edwin ES, Ponsankar A, Senthil-Nathan S, Selin-Rani S, Kalaivani K, Hunter WB, Duraipandiyan V, Al-Dhabi NA (2018b) Toxicological effects of chemical constituents from Piper against the environmental burden Aedes aegypti Liston and their impact on non-target toxicity evaluation against biomonitoring aquatic insects. Environ Sci Pollut Res Int 25:10434–10446PubMedGoogle Scholar
  56. Wagh V, Mishra P, Thakkar A, Shinde V, Sharma S, Padigaru M, Joshi K (2011) Antitumor activity of NPB001-05, an orally active inhibitor of Bcr-Abl tyrosine kinase. Front Biosci (Elite Ed) 3:1349–1364Google Scholar
  57. Wang CK, Peng CH (1996) The mutagenicities of alkaloids and N-nitrosoguvacoline from betel quid. Mutat Res 360:165–171PubMedGoogle Scholar
  58. Wu PF, Tseng HC, Chyau CC, Chen JH, Chou FP (2014) Piper betle leaf extracts induced human hepatocellular carcinoma Hep3B cell death via MAPKs regulating the p73 pathway in vitro and in vivo. Food Funct 5:3320–3328PubMedGoogle Scholar
  59. Young SC, Wang CJ, Hsu JD, Hsu JL, Chou FP (2006) Increased sensitivity of Hep G2 cells toward the cytotoxicity of cisplatin by the treatment of Piper betel leaf extract. Arch Toxicol 80:319–327PubMedGoogle Scholar
  60. Young SC, Wang CJ, Lin JJ, Peng PL, Hsu JL, Chou FP (2007) Protection effect of Piper betel leaf extract against carbon tetrachloride-induced liver fibrosis in rats. Arch Toxicol 81:45–55PubMedGoogle Scholar
  61. Yu CS, Huang AC, Yang JS, Yu CC, Lin CC, Chung HK, Huang YP, Chueh FS, Chung JG (2012) Safrole induces G0/G1 phase arrest via inhibition of cyclin E and provokes apoptosis through endoplasmic reticulum stress and mitochondrion-dependent pathways in human leukemia HL-60 cells. Anticancer Res 32:1671–1679PubMedGoogle Scholar

Copyright information

© Institute of Korean Medicine, Kyung Hee University 2019

Authors and Affiliations

  1. 1.Department of PharmacyRanada Prasad Shaha UniversityNarayanganjBangladesh
  2. 2.Department of PharmacyUniversity of Science and Technology ChittagongChittagongBangladesh
  3. 3.Department for Management of Science and Technology DevelopmentTon Duc Thang UniversityHo Chi Minh CityVietnam
  4. 4.Faculty of PharmacyTon Duc Thang UniversityHo Chi Minh CityVietnam

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