Kava Kava (Piper Methysticum)
Synopsis
Kava kava ‘Piper methysticum’(Kava), Vanatu’ya özgü bir bitki olup Güney Pasifik Adaları'nda uzun yıllardan beri yaygın olarak tüketilmekte ve özellikle bazı geleneksel törenlerde kullanılmaktadır. Bu bitki yatıştırıcı ve sakinleştirici etkiler gibi psikoaktif özellikler göstermektedir. Diğer ülkelerde de son zamanlarda anksiyolitik etkisinden faydalanılmaktadır. Kava aynı zamanda menopoz, uykusuzluk, konvülsiyonlar ve depresyonla ilişkili semptomları tedavi etmek için de kullanılmaktadır. Bu faydalı etkilerinin yanı sıra ilaç etkileşimleri, karaciğer toksisitesi, cilt yan etkileri ve diğer bazı yan etkileri kullanımını sınırlamaktadır. Kava ile yapılan genetik toksikoloji analizleri genel olarak negatif sonuçlar vermiştir. Ancak deney hayvanlarında kanserojen olduğuna dair çalışmalar vardır. Bu kanserojenik etkinin muhtemelen genotoksik olmayan bir yolla geliştiğine inanılmaktadır. Bununla birlikte Kava'nın kansere karşı tedavi edici ve kanseri önleyici potansiyeli de öne sürülmüştür. Çeşitli çalışmalarda farklı kanser modellerindeki etkileri değerlendirilmiştir. Akciğer, prostat, meme ve mesane dahil olmak üzere çeşitli kanser türlerinde antiproliferatif etkiler göstermiştir. Genel olarak, bu bölümde Kava'nın etkinliği ve istenmeyen etkileri çeşitli yönleri ile tartışılmıştır.
Kava kava, or ‘Piper methysticum’ is a plant native to Vanatu and has been widely consumed in the South Pacific Islands for many years, especially in some traditional ceremonies. This plant shows psychoactive properties such as sedative and calming effects. In other countries it has recently been used as an anxiolytic. Kava is also used to treat symptoms associated with menopause, insomnia, convulsions and depression. In addition to these beneficial effects, drug interactions, liver toxicity, skin side effects and other side effects are factors limiting its use. Genetic toxicology analyses with kava have generally yielded negative results. However, there are studies showing that it is carcinogenic in experimental animals. It is believed that this carcinogenic effect probably develops through a non-genotoxic pathway. However, the potential of kava to treat and prevent cancer has also been suggested. Many studies have evaluated its effects in different cancer models. It has shown antiproliferative effects in several cancer types, including lung, prostate, breast and bladder. Overall, the efficacy and adverse effects of kava are discussed in detail in this chapter.
References
E. Johnston, H. Rogers (Eds.), Hawaiian awa: views of an ethnobotanical treasure, Association for Hawaiian Awa, Hilo, Hawaii (2006)
Angelique F. Showman, Jonathan D. Baker, Christina Linares, et al. Contemporary Pacific and Western perspectives on `awa (Piper methysticum) toxicology, Fitoterapia,Volume 100, 2015, Pages 56-67, ISSN 0367-326X, https://doi.org/10.1016/j.fitote.2014.11.012.
Shaver J.H., Sosis R. How Does Male Ritual Behavior Vary Across the Lifespan?: An Examination of Fijian Kava Cere-monies. Hum. Nat. 2014;25:136–160. doi: 10.1007/s12110-014-9191-6.
Soares RB, Dinis-Oliveira RJ, Oliveira NG. An Updated Review on the Psychoactive, Toxic and Anticancer Properties of Kava. J Clin Med. 2022 Jul 12;11(14):4039. doi: 10.3390/jcm11144039. PMID: 35887801; PMCID: PMC9315573.
Pittler MH, Ernst E (2000) Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol 20:84–89
Leitzman P., et al. (2014). Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing O6-methylguanine DNA adduct in A/J mice. Cancer Prev. Res. (Phila)., 7, 86–96
Stickel F., Shouval D. Hepatotoxicity of herbal and dietary supplements: An update. Arch. Toxicol. 2015;89:851–865. doi: 10.1007/s00204-015-1471-3.
Singh Y.N., Singh N.N. Therapeutic Potential of Kava in the Treatment of Anxiety Disorders. CNS Drugs. 2002;16:731–743. doi: 10.2165/00023210-200216110-00002.
Bilia A.R., Scalise L., Bergonzi M.C., et al. Analysis of kavalactones from Piper methysticum (kava-kava) Anal. Technol. Biomed. Life Sci. 2004;812:203–214. doi: 10.1016/S1570-0232(04)00644-0.
Celentano A., Tran A., Testa C., et al. The protective effects of Kava (Piper methysticum) constituents in cancers: A systematic review. İou9p6y. 2019;48:510–529. doi: 10.1111/jop.12900.
Narayanapillai S.C., Balbo S., Leitzman P., et al. Dihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differentially reduces DNA damage in A/J mice. Carcinogenesis. 2014;35:2365–2372. doi: 10.1093/carcin/bgu149.
Hegazy N.H., Breitinger H.-G., Breitinger U. Kavalactones from Kava (Piper methysticum) root extract as modulators of recombinant human glycine receptors. Biol. Chem. 2019;400:1205–1215. doi: 10.1515/hsz-2019-0112.
Kuo Y.-F., Su Y.-Z., Tseng Y.-H., et al. Flavokawain B, a novel chalcone from Alpinia pricei Hayata with potent apoptotic activity: Involvement of ROS and GADD153 upstream of mitochondria-dependent apoptosis in HCT116 cells. Free Radic. Biol. Med. 2010;49:214–226. doi: 10.1016/j.freeradbiomed.2010.04.005.]
Lebot V., Do T., Legendre L. Detection of flavokavins (A, B, C) in cultivars of kava (Piper methysticum) using high performance thin layer chromatography (HPTLC) Food Chem. 2014;151:554–560. doi: 10.1016/j.foodchem.2013.11.120.
Kuchta K., de Nicola P., Schmidt M. Randomized, dose-controlled double-blind trial: Efficacy of an ethanolic kava (Piper methysticum rhizome) extract for the treatment of anxiety in elderly patients. Tradit. Kamp Med. 2017;5:3–10. doi: 10.1002/tkm2.1079.
Guo L., Li Q., Xia Q., et al. Analysis of gene expression changes of drug metabolizing enzymes in the livers of F344 rats following oral treatment with kava extract. Food Chem. Toxicol. 2009;47:433–442. doi: 10.1016/j.fct.2008.11.037.
Pantano F., Tittarelli R., Mannocchi G., et al. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat. Int. J. Mol. Sci. 2016;17:580. doi: 10.3390/ijms17040580.
Anke J, Razman I. Pharmacokinetic and pharmacodynamics drug interactions with kava (Piper methysticum Forst. f.). J Ethnopharmacol. 2004; 93: 153–160.
Weiss J, Sauer A, Frank A, et al. Extracts and kavalactones of Piper methysticum G. Forst (kava-kava) inhibit P-glycoprotein in vitro. Drug Metab Disp. 2005; 33: 1580–1583.
Herberg, KW. Effect of kava-special extract WS 1490 combined with ethyl alcohol on safety-relevant performance parameters. Blutalkohol. 1993; 30: 96–105.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans Some Drugs and Herbal Products. IARC Monogr. Eval. Carcinog. Risks Hum. 2016;108:7–419.
Einbond L., Negrin A., Kulakowski D., et al. Traditional preparations of kava (Piper methysticum) inhibit the growth of human colon cancer cells in vitro. Phytomedicine. 2017;24:1–13. doi: 10.1016/j.phymed.2016.11.002.
Leitzman P., Narayanapillai S.C., Balbo S., et al. Kava Blocks 4-(Methylnitrosamino)-1-(3-pyridyl)-1-Butanone–Induced Lung Tumorigenesis in Association with Reducing O6-methylguanine DNA Adduct in A/J Mice. Cancer Prev. Res. 2014;7:86–96. doi: 10.1158/1940- 6207.CAPR-13-0301.
Hu Q., Corral P., Narayanapillai S.C., et al. Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice. Chem. Res. Toxicol. 2020;33:1980–1988. doi: 10.1021/acs.chemrestox.0c00161.
Martin A.C., Johnston E., Xing C., et al. Measuring the Chemical and Cytotoxic Variability of Commercially Available Kava (Piper methysticum G. Forster) PLoS ONE. 2014;9:e111572. doi: 10.1371/journal.pone.0111572.
Johnson T.E., Hermanson D., Wang L.,et al. Lung Tumorigenesis Suppressing Effects of a Commercial Kava Extract and Its Selected Compounds in A/J Mice. Am. J. Chin. Med. 2011;39:727–742. doi: 10.1142/S0192415X11009202.
Wang Y., Narayanapillai S.C., Tessier K.M., et al. The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers. Cancer Prev. Res. 2020;13:483–492. doi: 10.1158/1940-6207.CAPR-19-0501.
Triolet J., Shaik A.A., Gallaher D., et al. Reduction in Colon Cancer Risk by Consumption of Kava or Kava Fractions in Carcinogen-Treated Rats. Nutr. Cancer. 2012;64:838–846. doi: 10.1080/01635581.2012.689917.
Jandial D.D., Krill L.S., Chen L., et al. Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin. Molecules. 2017;22:462. doi: 10.3390/molecules22030462.
Wang K., Zhang W., Wang Z., et al. Flavokawain A inhibits prostate cancer cells by inducing cell cycle arrest and cell apoptosis and regulating the glutamine metabolism pathway. J. Pharm. Biomed. Anal. 2020;186:113288. doi: 10.1016/j.jpba.2020.113288.
Abu N., Akhtar M.N., Yeap S.K., et al. Flavokawain A Induces Apoptosis in MCF-7 and MDA-MB231 and Inhibits the Metastatic Process In Vitro. PLoS ONE. 2014;9:e105244. doi: 10.1371/journal.pone.0105244.
Zi X., Simoneau A.R. Flavokawain A, a Novel Chalcone from Kava Extract, Induces Apoptosis in Bladder Cancer Cells by Involvement of Bax Protein-Dependent and Mitochondria-Dependent Apoptotic Pathway and Suppresses Tumor Growth in Mice. Cancer Res. 2005;65:3479–3486. doi: 10.1158/0008-5472.CAN-04-3803.
Liu Z., Xu X., Li X., et al. KAVA Chalcone, Flavokawain A, Inhibits Urothelial Tumorigenesis in the UPII-SV40T Transgenic Mouse Model. Cancer Prev. Res. 2013;6:1365–1375. doi: 10.1158/1940-6207.CAPR-13-0219.
Sakai T., Eskander R.N., Guo Y., et al. Flavokawain B, a kava chalcone, induces apoptosis in synovial sarcoma cell lines. J. Orthop. Res. 2012;30:1045–1050. doi: 10.1002/jor.22050.
Eskander R.N., Randall L.M., Sakai T., et al. Flavokawain B, a novel, naturally occurring chalcone, exhibits robust apoptotic effects and induces G2/M arrest of a uterine leiomyosarcoma cell line. J. Obstet. Gynaecol. Res. 2012;38:1086–1094. doi: 10.1111/j.1447-0756.2011.01841.x.
Abu N., Mohamed N.E., Yeap S.K., et al. In vivo antitumor and antimetastatic effects of flavokawain B in 4T1 breast cancer cell-challenged mice. Drug Des. Dev. Ther. 2015;9:1401–1417. doi: 10.2147/dddt.s67976
Abu N., Akhtar M.N., Yeap S.K., et al. Flavokawain B induced cytotoxicity in two breast cancer cell lines, MCF-7 and MDA-MB231 and inhibited the metastatic potential of MDA-MB231 via the regulation of several tyrosine kinases In vitro. BMC Complement. Altern. Med. 2016;16:86. doi: 10.1186/s12906-016-1046-8.
Hua R., Pei Y., Gu H., et al. Antitumor effects of flavokawain-B flavonoid in gemcitabine-resistant lung cancer cells are mediated via mitochondrial-mediated apoptosis, ROS production, cell migration and cell invasion inhibition and blocking of PI3K/AKT Signaling pathway. J. Buon. 2020;25:262–267.
Phang C.-W., Karsani S.A., Sethi G., Malek S.N.A. Flavokawain C Inhibits Cell Cycle and Promotes Apoptosis, Associated with Endoplasmic Reticulum Stress and Regulation of MAPKs and Akt Signaling Pathways in HCT 116 Human Colon Carcinoma Cells. PLoS ONE. 2016;11:e0148775. doi: 10.1371/journal.pone.0148775.
Phang C.-W., Karsani S.A., Malek S.N.A. Induction of apoptosis and cell cycle arrest by flavokawain C on HT-29 human colon adenocarcinoma via enhancement of reactive oxygen species generation, upregulation of p21, p27, and Gadd153, and inactivation of inhibitor of apoptosis proteins. Pharmacogn. Mag. 2017;13:S321–S328. doi: 10.4103/0973-1296.210180.
Wang J., Qi Q., Zhou W., et al. Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy. Autophagy. 2018;14:2007–2022. doi: 10.1080/15548627.2018.1501133.
Hseu Y.-C., Lin R.-W., Shen Y.-C., et al. Flavokawain B and Doxorubicin Work Synergistically to Impede the Propagation of Gastric Cancer Cells via ROS-Mediated Apoptosis and Autophagy Pathways. Cancers. 2020;12:2475. doi: 10.3390/cancers12092475.
Liu Z., Ha U.S., Yu K., et al. Kavalactone yangonin induces autophagy and sensitizes bladder cancer cells to flavokawain A and docetaxel via inhibition of the mTOR pathway. J. Biomed. Res. 2017;31:408–418. doi: 10.7555/jbr.31.20160160.
Hecht S.S., Kassie F., Hatsukami D.K. Chemoprevention of lung carcinogenesis in addicted smokers and ex-smokers. Nat. Cancer. 2009;9:476–488. doi: 10.1038/nrc2674.
Hu Q., Corral P., Narayanapillai S.C., Leitzman P., et al. Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice. Chem. Res. Toxicol. 2020;33:1980–1988. doi: 10.1021/acs.chemrestox.0c00161.
Pan H., Liu F., Wang J., et al. Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway. Mol. Carcinog. 2020;59:575–589. doi: 10.1002/mc.23182.
Humberston C.L., Akhtar J., Krenzelok E.P. Acute Hepatitis Induced by Kava Kava. J. Toxicol. Clin. Toxicol. 2003;41:109–113. doi: 10.1081/CLT-120019123.
Showman A.F., Baker J.D., Linares C., et al. Contemporary Pacific and Western perspectives on ’awa (Piper methysticum) toxicology. Fitoterapia. 2015;100:56–67. doi: 10.1016/j.fitote.2014.11.012.
World Health Organization (WHO) Assessments of the Risk of Hepatotoxicity with Kava Products. WHO Document Production Services; Geneva, Switzerland: 2007.
Ulbricht C., Basch E., Boon H., et al. Safety review of kava (Piper methysticum) by the Natural Standard Research Collaboration. Expert Opin. Drug Saf. 2005;4:779–794. doi: 10.1517/14740338.4.4.779.
Nerurkar P.V., Dragull K., Tang C.-S. In Vitro Toxicity of Kava Alkaloid, Pipermethystine, in HepG2 Cells Compared to Kavalactones. Toxicol. Sci. 2004;79:106–111. doi: 10.1093/toxsci/kfh067.
Tugcu G., Kırmızıbekmez H., Aydın A. The integrated use of in silico methods for the hepatotoxicity potential of Piper methysticum. Food Chem. Toxicol. 2020;145:111663. doi: 10.1016/j.fct.2020.111663.
Zhou P., Gross S., Liu J.-H., et al. Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-κB and MAPK signaling pathways. FASEB J. 2010;24:4722–4732. doi: 10.1096/fj.10-163311.
Narayanapillai S.C., Leitzman P., O’Sullivan M.G., et al. Flavokawains A and B in Kava, Not Dihydromethysticin, Potentiate Acetaminophen-Induced Hepatotoxicity in C57BL/6 Mice. Chem. Res. Toxicol. 2014;27:1871–1876. doi: 10.1021/tx5003194.
Teschke R., Qiu S.X., Lebot V. Herbal hepatotoxicity by kava: Update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits. Dig. Liver Dis. 2011;43:676–681. doi: 10.1016/j.dld.2011.01.018.
Rowe A., Ramzan I. Are Mould Hepatotoxins Responsible for Kava Hepatotoxicity? Phytotherapy Res. 2012;26:1768–1770. doi: 10.1002/ptr.4620.
Norton S.A., Ruze P. Kava dermopathy. J. Am. Acad. Dermatol. 1994;31:89–97. doi: 10.1016/S0190-9622(94)70142-3.
White C.M. The Pharmacology, Pharmacokinetics, Efficacy, and Adverse Events Associated with Kava. J. Clin. Pharmacol. 2018;58:1396–1405. doi: 10.1002/jcph.1263.
Sarris J., Stough C., Teschke R., et al. Kava for the Treatment of Generalized Anxiety Disorder RCT: Analysis of Adverse Reactions, Liver Function, Addiction, and Sexual Effects. Phytotherapy Res. 2013;27:1723–1728. doi: 10.1002/ptr.4916.
Baker J.D. Tradition and toxicity: Evidential cultures in the kava safety debate. Soc. Stud. Sci. 2011;41:361–384. doi: 10.1177/0306312710395341.
Meseguer E., Taboada R., Sánchez V., et al. Life-threatening parkinsonism induced by kava-kava. Mov. Disord. 2002;17:195–196. doi: 10.1002/mds.1268.
Vignier N., Lert F., Salomon C., et al. Kava drinking associated with suicidal behaviour among young Kanaks using kava in New Caledonia. Aust. N. Z. J. Public Health. 2011;35:427–433. doi: 10.1111/j.1753-6405.2011.00737.x.
Sarris J., Laporte E., Scholey A., et al. Does a Medicinal Dose of Kava Impair Driving? A Randomized, Placebo-Controlled, Double-Blind Study. Traffic Inj. Prev. 2013;14:13–17. doi: 10.1080/15389588.2012.682233.
Foo H., Lemon J. Acute effects of kava, alone or in combination with alcohol, on subjective measures of impairment and intoxication and on cognitive performance. Drug Alcohol Rev. 1997;16:147–155. doi: 10.1080/09595239700186441.
Wainiqolo I., Kafoa B., Kool B., et al. Driving following Kava Use and Road Traffic Injuries: A Population-Based Case-Control Study in Fiji (TRIP 14) PLoS ONE. 2016;11:e0149719. doi: 10.1371/journal.pone.0149719.
Angelique F. Showman, Jonathan D. Baker, Christina Linares, et al. Contemporary Pacific and Western perspectives on `awa (Piper methysticum) toxicology, Fitoterapia,Volume 100, 2015, Pages 56-67, ISSN 0367-326X, https://doi.org/10.1016/j.fitote.2014.11.012.
Shaver J.H., Sosis R. How Does Male Ritual Behavior Vary Across the Lifespan?: An Examination of Fijian Kava Cere-monies. Hum. Nat. 2014;25:136–160. doi: 10.1007/s12110-014-9191-6.
Soares RB, Dinis-Oliveira RJ, Oliveira NG. An Updated Review on the Psychoactive, Toxic and Anticancer Properties of Kava. J Clin Med. 2022 Jul 12;11(14):4039. doi: 10.3390/jcm11144039. PMID: 35887801; PMCID: PMC9315573.
Pittler MH, Ernst E (2000) Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol 20:84–89
Leitzman P., et al. (2014). Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing O6-methylguanine DNA adduct in A/J mice. Cancer Prev. Res. (Phila)., 7, 86–96
Stickel F., Shouval D. Hepatotoxicity of herbal and dietary supplements: An update. Arch. Toxicol. 2015;89:851–865. doi: 10.1007/s00204-015-1471-3.
Singh Y.N., Singh N.N. Therapeutic Potential of Kava in the Treatment of Anxiety Disorders. CNS Drugs. 2002;16:731–743. doi: 10.2165/00023210-200216110-00002.
Bilia A.R., Scalise L., Bergonzi M.C., et al. Analysis of kavalactones from Piper methysticum (kava-kava) Anal. Technol. Biomed. Life Sci. 2004;812:203–214. doi: 10.1016/S1570-0232(04)00644-0.
Celentano A., Tran A., Testa C., et al. The protective effects of Kava (Piper methysticum) constituents in cancers: A systematic review. İou9p6y. 2019;48:510–529. doi: 10.1111/jop.12900.
Narayanapillai S.C., Balbo S., Leitzman P., et al. Dihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differentially reduces DNA damage in A/J mice. Carcinogenesis. 2014;35:2365–2372. doi: 10.1093/carcin/bgu149.
Hegazy N.H., Breitinger H.-G., Breitinger U. Kavalactones from Kava (Piper methysticum) root extract as modulators of recombinant human glycine receptors. Biol. Chem. 2019;400:1205–1215. doi: 10.1515/hsz-2019-0112.
Kuo Y.-F., Su Y.-Z., Tseng Y.-H., et al. Flavokawain B, a novel chalcone from Alpinia pricei Hayata with potent apoptotic activity: Involvement of ROS and GADD153 upstream of mitochondria-dependent apoptosis in HCT116 cells. Free Radic. Biol. Med. 2010;49:214–226. doi: 10.1016/j.freeradbiomed.2010.04.005.]
Lebot V., Do T., Legendre L. Detection of flavokavins (A, B, C) in cultivars of kava (Piper methysticum) using high performance thin layer chromatography (HPTLC) Food Chem. 2014;151:554–560. doi: 10.1016/j.foodchem.2013.11.120.
Kuchta K., de Nicola P., Schmidt M. Randomized, dose-controlled double-blind trial: Efficacy of an ethanolic kava (Piper methysticum rhizome) extract for the treatment of anxiety in elderly patients. Tradit. Kamp Med. 2017;5:3–10. doi: 10.1002/tkm2.1079.
Guo L., Li Q., Xia Q., et al. Analysis of gene expression changes of drug metabolizing enzymes in the livers of F344 rats following oral treatment with kava extract. Food Chem. Toxicol. 2009;47:433–442. doi: 10.1016/j.fct.2008.11.037.
Pantano F., Tittarelli R., Mannocchi G., et al. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat. Int. J. Mol. Sci. 2016;17:580. doi: 10.3390/ijms17040580.
Anke J, Razman I. Pharmacokinetic and pharmacodynamics drug interactions with kava (Piper methysticum Forst. f.). J Ethnopharmacol. 2004; 93: 153–160.
Weiss J, Sauer A, Frank A, et al. Extracts and kavalactones of Piper methysticum G. Forst (kava-kava) inhibit P-glycoprotein in vitro. Drug Metab Disp. 2005; 33: 1580–1583.
Herberg, KW. Effect of kava-special extract WS 1490 combined with ethyl alcohol on safety-relevant performance parameters. Blutalkohol. 1993; 30: 96–105.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans Some Drugs and Herbal Products. IARC Monogr. Eval. Carcinog. Risks Hum. 2016;108:7–419.
Einbond L., Negrin A., Kulakowski D., et al. Traditional preparations of kava (Piper methysticum) inhibit the growth of human colon cancer cells in vitro. Phytomedicine. 2017;24:1–13. doi: 10.1016/j.phymed.2016.11.002.
Leitzman P., Narayanapillai S.C., Balbo S., et al. Kava Blocks 4-(Methylnitrosamino)-1-(3-pyridyl)-1-Butanone–Induced Lung Tumorigenesis in Association with Reducing O6-methylguanine DNA Adduct in A/J Mice. Cancer Prev. Res. 2014;7:86–96. doi: 10.1158/1940- 6207.CAPR-13-0301.
Hu Q., Corral P., Narayanapillai S.C., et al. Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice. Chem. Res. Toxicol. 2020;33:1980–1988. doi: 10.1021/acs.chemrestox.0c00161.
Martin A.C., Johnston E., Xing C., et al. Measuring the Chemical and Cytotoxic Variability of Commercially Available Kava (Piper methysticum G. Forster) PLoS ONE. 2014;9:e111572. doi: 10.1371/journal.pone.0111572.
Johnson T.E., Hermanson D., Wang L.,et al. Lung Tumorigenesis Suppressing Effects of a Commercial Kava Extract and Its Selected Compounds in A/J Mice. Am. J. Chin. Med. 2011;39:727–742. doi: 10.1142/S0192415X11009202.
Wang Y., Narayanapillai S.C., Tessier K.M., et al. The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers. Cancer Prev. Res. 2020;13:483–492. doi: 10.1158/1940-6207.CAPR-19-0501.
Triolet J., Shaik A.A., Gallaher D., et al. Reduction in Colon Cancer Risk by Consumption of Kava or Kava Fractions in Carcinogen-Treated Rats. Nutr. Cancer. 2012;64:838–846. doi: 10.1080/01635581.2012.689917.
Jandial D.D., Krill L.S., Chen L., et al. Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin. Molecules. 2017;22:462. doi: 10.3390/molecules22030462.
Wang K., Zhang W., Wang Z., et al. Flavokawain A inhibits prostate cancer cells by inducing cell cycle arrest and cell apoptosis and regulating the glutamine metabolism pathway. J. Pharm. Biomed. Anal. 2020;186:113288. doi: 10.1016/j.jpba.2020.113288.
Abu N., Akhtar M.N., Yeap S.K., et al. Flavokawain A Induces Apoptosis in MCF-7 and MDA-MB231 and Inhibits the Metastatic Process In Vitro. PLoS ONE. 2014;9:e105244. doi: 10.1371/journal.pone.0105244.
Zi X., Simoneau A.R. Flavokawain A, a Novel Chalcone from Kava Extract, Induces Apoptosis in Bladder Cancer Cells by Involvement of Bax Protein-Dependent and Mitochondria-Dependent Apoptotic Pathway and Suppresses Tumor Growth in Mice. Cancer Res. 2005;65:3479–3486. doi: 10.1158/0008-5472.CAN-04-3803.
Liu Z., Xu X., Li X., et al. KAVA Chalcone, Flavokawain A, Inhibits Urothelial Tumorigenesis in the UPII-SV40T Transgenic Mouse Model. Cancer Prev. Res. 2013;6:1365–1375. doi: 10.1158/1940-6207.CAPR-13-0219.
Sakai T., Eskander R.N., Guo Y., et al. Flavokawain B, a kava chalcone, induces apoptosis in synovial sarcoma cell lines. J. Orthop. Res. 2012;30:1045–1050. doi: 10.1002/jor.22050.
Eskander R.N., Randall L.M., Sakai T., et al. Flavokawain B, a novel, naturally occurring chalcone, exhibits robust apoptotic effects and induces G2/M arrest of a uterine leiomyosarcoma cell line. J. Obstet. Gynaecol. Res. 2012;38:1086–1094. doi: 10.1111/j.1447-0756.2011.01841.x.
Abu N., Mohamed N.E., Yeap S.K., et al. In vivo antitumor and antimetastatic effects of flavokawain B in 4T1 breast cancer cell-challenged mice. Drug Des. Dev. Ther. 2015;9:1401–1417. doi: 10.2147/dddt.s67976
Abu N., Akhtar M.N., Yeap S.K., et al. Flavokawain B induced cytotoxicity in two breast cancer cell lines, MCF-7 and MDA-MB231 and inhibited the metastatic potential of MDA-MB231 via the regulation of several tyrosine kinases In vitro. BMC Complement. Altern. Med. 2016;16:86. doi: 10.1186/s12906-016-1046-8.
Hua R., Pei Y., Gu H., et al. Antitumor effects of flavokawain-B flavonoid in gemcitabine-resistant lung cancer cells are mediated via mitochondrial-mediated apoptosis, ROS production, cell migration and cell invasion inhibition and blocking of PI3K/AKT Signaling pathway. J. Buon. 2020;25:262–267.
Phang C.-W., Karsani S.A., Sethi G., Malek S.N.A. Flavokawain C Inhibits Cell Cycle and Promotes Apoptosis, Associated with Endoplasmic Reticulum Stress and Regulation of MAPKs and Akt Signaling Pathways in HCT 116 Human Colon Carcinoma Cells. PLoS ONE. 2016;11:e0148775. doi: 10.1371/journal.pone.0148775.
Phang C.-W., Karsani S.A., Malek S.N.A. Induction of apoptosis and cell cycle arrest by flavokawain C on HT-29 human colon adenocarcinoma via enhancement of reactive oxygen species generation, upregulation of p21, p27, and Gadd153, and inactivation of inhibitor of apoptosis proteins. Pharmacogn. Mag. 2017;13:S321–S328. doi: 10.4103/0973-1296.210180.
Wang J., Qi Q., Zhou W., et al. Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy. Autophagy. 2018;14:2007–2022. doi: 10.1080/15548627.2018.1501133.
Hseu Y.-C., Lin R.-W., Shen Y.-C., et al. Flavokawain B and Doxorubicin Work Synergistically to Impede the Propagation of Gastric Cancer Cells via ROS-Mediated Apoptosis and Autophagy Pathways. Cancers. 2020;12:2475. doi: 10.3390/cancers12092475.
Liu Z., Ha U.S., Yu K., et al. Kavalactone yangonin induces autophagy and sensitizes bladder cancer cells to flavokawain A and docetaxel via inhibition of the mTOR pathway. J. Biomed. Res. 2017;31:408–418. doi: 10.7555/jbr.31.20160160.
Hecht S.S., Kassie F., Hatsukami D.K. Chemoprevention of lung carcinogenesis in addicted smokers and ex-smokers. Nat. Cancer. 2009;9:476–488. doi: 10.1038/nrc2674.
Hu Q., Corral P., Narayanapillai S.C., Leitzman P., et al. Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice. Chem. Res. Toxicol. 2020;33:1980–1988. doi: 10.1021/acs.chemrestox.0c00161.
Pan H., Liu F., Wang J., et al. Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway. Mol. Carcinog. 2020;59:575–589. doi: 10.1002/mc.23182.
Humberston C.L., Akhtar J., Krenzelok E.P. Acute Hepatitis Induced by Kava Kava. J. Toxicol. Clin. Toxicol. 2003;41:109–113. doi: 10.1081/CLT-120019123.
Showman A.F., Baker J.D., Linares C., et al. Contemporary Pacific and Western perspectives on ’awa (Piper methysticum) toxicology. Fitoterapia. 2015;100:56–67. doi: 10.1016/j.fitote.2014.11.012.
World Health Organization (WHO) Assessments of the Risk of Hepatotoxicity with Kava Products. WHO Document Production Services; Geneva, Switzerland: 2007.
Ulbricht C., Basch E., Boon H., et al. Safety review of kava (Piper methysticum) by the Natural Standard Research Collaboration. Expert Opin. Drug Saf. 2005;4:779–794. doi: 10.1517/14740338.4.4.779.
Nerurkar P.V., Dragull K., Tang C.-S. In Vitro Toxicity of Kava Alkaloid, Pipermethystine, in HepG2 Cells Compared to Kavalactones. Toxicol. Sci. 2004;79:106–111. doi: 10.1093/toxsci/kfh067.
Tugcu G., Kırmızıbekmez H., Aydın A. The integrated use of in silico methods for the hepatotoxicity potential of Piper methysticum. Food Chem. Toxicol. 2020;145:111663. doi: 10.1016/j.fct.2020.111663.
Zhou P., Gross S., Liu J.-H., et al. Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-κB and MAPK signaling pathways. FASEB J. 2010;24:4722–4732. doi: 10.1096/fj.10-163311.
Narayanapillai S.C., Leitzman P., O’Sullivan M.G., et al. Flavokawains A and B in Kava, Not Dihydromethysticin, Potentiate Acetaminophen-Induced Hepatotoxicity in C57BL/6 Mice. Chem. Res. Toxicol. 2014;27:1871–1876. doi: 10.1021/tx5003194.
Teschke R., Qiu S.X., Lebot V. Herbal hepatotoxicity by kava: Update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits. Dig. Liver Dis. 2011;43:676–681. doi: 10.1016/j.dld.2011.01.018.
Rowe A., Ramzan I. Are Mould Hepatotoxins Responsible for Kava Hepatotoxicity? Phytotherapy Res. 2012;26:1768–1770. doi: 10.1002/ptr.4620.
Norton S.A., Ruze P. Kava dermopathy. J. Am. Acad. Dermatol. 1994;31:89–97. doi: 10.1016/S0190-9622(94)70142-3.
White C.M. The Pharmacology, Pharmacokinetics, Efficacy, and Adverse Events Associated with Kava. J. Clin. Pharmacol. 2018;58:1396–1405. doi: 10.1002/jcph.1263.
Sarris J., Stough C., Teschke R., et al. Kava for the Treatment of Generalized Anxiety Disorder RCT: Analysis of Adverse Reactions, Liver Function, Addiction, and Sexual Effects. Phytotherapy Res. 2013;27:1723–1728. doi: 10.1002/ptr.4916.
Baker J.D. Tradition and toxicity: Evidential cultures in the kava safety debate. Soc. Stud. Sci. 2011;41:361–384. doi: 10.1177/0306312710395341.
Meseguer E., Taboada R., Sánchez V., et al. Life-threatening parkinsonism induced by kava-kava. Mov. Disord. 2002;17:195–196. doi: 10.1002/mds.1268.
Vignier N., Lert F., Salomon C., et al. Kava drinking associated with suicidal behaviour among young Kanaks using kava in New Caledonia. Aust. N. Z. J. Public Health. 2011;35:427–433. doi: 10.1111/j.1753-6405.2011.00737.x.
Sarris J., Laporte E., Scholey A., et al. Does a Medicinal Dose of Kava Impair Driving? A Randomized, Placebo-Controlled, Double-Blind Study. Traffic Inj. Prev. 2013;14:13–17. doi: 10.1080/15389588.2012.682233.
Foo H., Lemon J. Acute effects of kava, alone or in combination with alcohol, on subjective measures of impairment and intoxication and on cognitive performance. Drug Alcohol Rev. 1997;16:147–155. doi: 10.1080/09595239700186441.
Wainiqolo I., Kafoa B., Kool B., et al. Driving following Kava Use and Road Traffic Injuries: A Population-Based Case-Control Study in Fiji (TRIP 14) PLoS ONE. 2016;11:e0149719. doi: 10.1371/journal.pone.0149719.
Pages
199-208
Published
March 11, 2024
Copyright (c) 2024 Academician Publishing Book Portal
License
LicenseHow to Cite
1.
Garip Bilen Y. Kava Kava (Piper Methysticum). In: Sakin A, editor. Kanser Hastalarının Başvurduğu Geleneksel ve Tamamlayıcı Tedaviler - Tıbbi Onkolog Gözü ile Bakış ve Onkolojik İlaçlarla Etkileşim [Internet]. Türkiye: Academician Publishing Book DOI Portal; 2024 [cited 2026 Jul. 13]. pp. 199-208. Available from: https://omp35.books.akademisyen.net/index.php/akya/catalog/book/2380/chapter/13917
