RSS-Feed abonnieren
DOI: 10.1055/a-0642-1966
Safety and Toxicology of Magnolol and Honokiol
Publikationsverlauf
received 23. März 2018
revised 29. Mai 2018
accepted 06. Juni 2018
Publikationsdatum:
20. Juni 2018 (online)
![](https://www.thieme-connect.de/media/plantamedica/201816/lookinside/thumbnails/10-1055-a-0642-1966_pmc0244-1.jpg)
Abstract
Magnolia officinalis and Magnolia obovata bark extracts have been used for thousands of years in Chinese and Japanese traditional medicines and are still widely employed as herbal preparations for their sedative, antioxidant, anti-inflammatory, antibiotic, and antispastic effects. Neolignans, particularly magnolol and honokiol, are the main substances responsible for the beneficial properties of the magnolia bark extract (MBE). The content of magnolol and honokiol in MBE depends on different factors, including the Magnolia plant species, the area of origin, the part of the plant employed, and the method used to prepare the extract. The biological and pharmacological activities of magnolol and honokiol have been extensively investigated. Here we review the safety and toxicological properties of magnolol and honokiol as pure substances or as components of concentrated MBE, including the potential side-effects in humans after oral intake. In vitro and in vivo genotoxicity studies indicated that concentrated MBE has no mutagenic and genotoxic potential, while a subchronic study performed according to OECD (Organisation for Economic Co-operation and Development) guidelines established a no adverse effect level for concentrated MBE > 240 mg/kg b.w/d. Similar to other dietary polyphenols, magnolol and honokiol are subject to glucuronidation, and despite a relatively quick clearance, an interaction with pharmaceutical active principles or other herbal constituents cannot be excluded. However, intervention trials employing concentrated MBE for up to 1 y did not report adverse effects. In conclusion, over the recent years different food safety authorities evaluated magnolol and honokiol and considered them safe.
Supporting Information
- Supporting Information
Additional details on the bibliographic strategy are provided as Supplementary Information.
-
References
- 1 Tsai TH, Chou CJ, Lee TF, Wang LCH, Chen CF. Pharmacokinetic and pharmacodynamic studies of magnolol after oral administration in rats. Pharmaceutical Sciences 1996; 2: 191-193
- 2 Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT. Therapeutic applications of compounds in the magnolia family. Pharmacol Ther 2011; 130: 157-176
- 3 Poivre M, Duez P. Biological activity and toxicity of the Chinese herb Magnolia officinalis Rehder & E. Wilson (Houpo) and its constituents. J Zhejiang Univ Sci B 2017; 18: 194-214
- 4 Hsieh MT, Chueh FY, Lin MT. Magnolol decreases body temperature by reducing 5-hydroxytryptamine release in the rat hypothalamus. Clin Exp Pharmacol Physiol 1998; 25: 813-817
- 5 Wu L, Zou H, Xia W, Dong Q, Wang L. Role of magnolol in the proliferation of vascular smooth muscle cells. Herz 2015; 40: 542-548
- 6 Herrmann D, Schreiber A, Ciotkowska A, Strittmatter F, Waidelich R, Stief CG, Gratzke C, Hennenberg M. Honokiol, a constituent of Magnolia species, inhibits adrenergic contraction of human prostate strips and induces stromal cell death. Prostate Int 2014; 2: 140-146
- 7 Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097
- 8 Centre for Reviews and Dissemination. Systematic Reviews: CRDʼs Guidance for Undertaking Reviews in Health Care: Centre for Reviews and Dissemination. Layerthorpe: York Publishing Services; 2009
- 9 Yahara S, Nishiyori T, Kohda A, Nohara T, Nishioka I. Isolation and characterization of phenolic compounds from magnoliae cortex produced in China. Chem Pharm Bull (Tokyo) 1991; 39: 2024-2036
- 10 Jin-Ping S, Zai-Kang T, Ri-Yan Z. Study of quality of Hou Po. China J Chinese Trad Med 2000; 25: 466-469
- 11 Zai-Kang T, Jin-Ping S, Rao L. Study on variation and inheritance of phenolic compound concentrations in Magnolia officinalis of different seed sources. Forest Res 2000; 13: 257-261
- 12 Matsuda H, Kageura T, Oda M, Morikawa T, Sakamoto Y, Yoshikawa M. Effects of constituents from the bark of Magnolia obovata on nitric oxide production in lipopolysaccharide-activated macrophages. Chem Pharm Bull (Tokyo) 2001; 49: 716-720
- 13 Min BS. Anti-complement activity of phenolic compounds from the stem bark of Magnolia obovate . Nat Prod Sci 2008; 14: 196-201
- 14 Choi NH, Choi GJ, Min BS, Jang KS, Choi YH, Kang MS, Park MS, Choi JE, Bae BK, Kim JC. Effects of neolignans from the stem bark of Magnolia obovata on plant pathogenic fungi. J Appl Microbiol 2009; 106: 2057-2063
- 15 Lee YK, Yuk DY, Kim TI, Kim YH, Kim KT, Kim KH, Lee BJ, Nam SY, Hong JT. Protective effect of the ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on scopolamine-induced memory impairment and the inhibition of acetylcholinesterase activity. J Nat Med 2009; 63: 274-282
- 16 Jiang Y, Vaysse J, Gilard V, Balayssac S, Dejean S, Malet-Martino M, David B, Fiorini C, Barbin Y. Quality assessment of commercial Magnoliae officinalis Cortex by (1)H-NMR-based metabolomics and HPLC methods. Phytochem Anal 2012; 23: 387-395
- 17 Zhao Z, Hu M, Sashida Y, Tang X. Pharmacognostical Studies on the magnolia bark (3). Determination of magnolol and honokiol in “Hou Po” (Cortex Magnoliae) prepared from the bark of different age. Jap J Pharmacogn 1991; 45: 145-147
- 18 Lee S, Khoo C, Halstead CW, Huynh T, Bensoussan A. Liquid chromatographic determination of honokiol and magnolol in Hou Po (Magnolia officinalis) as the raw herb and dried aqueous extract. J AOAC Int 2007; 90: 1210-1218
- 19 Li N, Song Y, Zhang W, Wang W, Chen J, Wong AW, Roberts A. Evaluation of the in vitro and in vivo genotoxicity of magnolia bark extract. Regul Toxicol Pharmacol 2007; 49: 154-159
- 20 Zhang B, Maniatis T, Song Y, Zhang W, Zhang X, Li N, Chen J, Wong AW, Roberts A. Evaluation of magnolia bark extract in chromosomal aberration assays. Mutat Res 2008; 654: 133-137
- 21 Nachtergael A, Poivre M, Belayew A, Duez P. In vitro genotoxicity tests point to an unexpected and harmful effect of a magnolia and aristolochia association. J Ethnopharmacol 2015; 174: 178-186
- 22 Bai X, Cerimele F, Ushio-Fukai M, Waqas M, Campbell PM, Govindarajan B, Der CJ, Battle T, Frank DA, Ye K, Murad E, Dubiel W, Soff G, Arbiser JL. Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo . J Biol Chem 2003; 278: 35501-35507
- 23 Fried LE, Arbiser JL. Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxid Redox Signal 2009; 11: 1139-1148
- 24 Fujita S, Taira J. Biphenyl compounds are hydroxyl radical scavengers: their effective inhibition for UV-induced mutation in Salmonella typhimurium TA102. Free Rad Biol Med 1994; 17: 273-277
- 25 Saito J, Sakai Y, Nagase H. In vitro anti-mutagenic effect of magnolol against direct and indirect mutagens. Mutat Res 2006; 609: 68-73
- 26 Hattori M, Endo Y, Takebe S, Kobashi K, Fukasaku N, Namba T. Metabolism of magnolol from magnoliae cortex. II. Absorption, metabolism and excretion of [ring-14C]magnolol in rats. Chem Pharm Bull (Tokyo) 1986; 34: 158-167
- 27 Yong-Hua M, Jia-Nan Y, Noboru F, Masao H, Tsuneo N. Metabolism of magnolol from magnoliae cortex (IV): enterohepatic circulation and gastrointestinal excretion of (ring-14C)magnolol in rats. Jap J Pharmacogn 1988; 42: 130-134
- 28 Bohmdorfer M, Maier-Salamon A, Taferner B, Reznicek G, Thalhammer T, Hering S, Hufner A, Schuhly W, Jager W. In vitro metabolism and disposition of honokiol in rat and human livers. J Pharm Sci 2011; 100: 3506-3516
- 29 Dong Y, Tang M, Song H, Li R, Wang C, Ye H, Qiu N, Zhang Y, Chen L, Wei Y. Characterization of metabolic profile of honokiol in rat feces using liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and (13)C stable isotope labeling. J Chromatogr B Analyt Technol Biomed Life Sci 2014; 953 – 954: 20-29
- 30 Lai H, Tang M, Liu J, Dong Y, Qiu N, Li S, Ma L, Yang J, Song H, Zhang Y, Peng A, Chen L. Identification of honokiol metabolites in rats by the method of stable isotope cluster technique and ultra-high performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 931: 157-163
- 31 Liu J, Tang M, Lai H, Dong Y, Xie C, Ye H, Ma L, Qiu N, Li Y, Cai L, Chen L. Identification of metabolites of honokiol in rat urine using 13C stable isotope labeling and liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. J Chromatogr A 2013; 1295: 48-56
- 32 Jeong HU, Kim JH, Kong TY, Choi WG, Lee HS. Comparative metabolism of honokiol in mouse, rat, dog, monkey, and human hepatocytes. Arch Pharm Res 2016; 39: 516-530
- 33 Sang S, Lambert JD, Ho CT, Yang CS. The chemistry and biotransformation of tea constituents. Pharmacol Res 2011; 64: 87-99
- 34 Maier-Salamon A, Bohmdorfer M, Thalhammer T, Szekeres T, Jaeger W. Hepatic glucuronidation of resveratrol: interspecies comparison of enzyme kinetic profiles in human, mouse, rat, and dog. Drug Met Pharmacokinet 2011; 26: 364-373
- 35 Tsai TH, Chou CJ, Chen CF. Pharmacokinetics and brain distribution of magnolol in the rat after intravenous bolus injection. J Pharm Pharmacol 1996; 48: 57-59
- 36 Tsai TH, Chou CJ, Cheng FC, Chen CF. Pharmacokinetics of honokiol after intravenous administration in rats assessed using high-performance liquid chromatography. J Chromatogr B Biomed Appl 1994; 655: 41-45
- 37 Lin SP, Tsai SY, Lee Chao PD, Chen YC, Hou YC. Pharmacokinetics, bioavailability, and tissue distribution of magnolol following single and repeated dosing of magnolol to rats. Planta Med 2011; 77: 1800-1805
- 38 Tsai TH, Chou CJ, Chen CF. Glucuronidation of magnolol assessed using HPLC/fluorescence. Planta Med 1995; 61: 491-492
- 39 Homma M, Oka K, Kobayashi H, Niitsuma T, Yamamoto S, Itoh H, Takahashi N. Liquid chromatographic determination of magnolol in urine collected from volunteers after a single dose of saiboku-to, an oriental herbal medicine for bronchial asthma. J Pharm Pharmacol 1993; 45: 839-841
- 40 Jun-Jun W, Xiao-Lei M, Jing-Ya C, Yong C. The pharmacokinetics and tissue distribution of honokiol and its metabolites in rats. Eur J Drug Metab Pharmacokinet 2016; 41: 587-594
- 41 Liu Y, Wang D, Yang G, Shi Q, Feng F. Comparative pharmacokinetics and brain distribution of magnolol and honokiol after oral administration of Magnolia officinalis cortex extract and its compatibility with other herbal medicines in Zhi-Zi-Hou-Po decoction to rats. Biomed Chromatogr 2016; 30: 369-375
- 42 Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2008; 22: 659-661
- 43 Cheng Z. Comparative studies on the interactions of honokiol and magnolol with human serum albumin. J Pharm Biomed Anal 2012; 66: 240-251
- 44 Chang HM, But HM. eds. Pharmacology and Applications of Chinese Materia Medica, vol. II. Singapore: World Scientific Publishing Co Pte Ltd; 1986: 878-880
- 45 Ueng T, Kang JJ, Wang HW, Lin PC. An overview of the toxicology of commonly used traditional Chinese medicine. Yao WuShih Pʼin Fen Hsi (J Food Drug Anal) 1997; 5: 241-264
- 46 Yang H, Chen CF. Subacute toxicity of 15 commonly used Chinese drugs (II). J Food Drug Anal 1997; 5: 355-380
- 47 Cheng Y, Nuan J, Lin Z, Li Z, Ming G, Zhu-Xin Y. Impairment of kidney induced by methanol extract of Magnolia officinalis after single or chronic administration in mice. Pharmaceut Care Res 2003; 3: 156-159
- 48 Yang HY, Chen CF. Pharmacology and toxicology of herbal medicine: subacute toxicity of commonly used Chinese drugs. J Toxicol Sci 1998; 23 (Suppl. 02) 229-233
- 49 Liu Z, Zhang X, Cui W, Zhang X, Li N, Chen J, Wong AW, Roberts A. Evaluation of short-term and subchronic toxicity of magnolia bark extract in rats. Regul Toxicol Pharmacol 2007; 49: 160-171
- 50 Food and Drug Administration. Good Laboratory Practice for Nonclinical Laboratory Studies; Proposed Rule. Available at: https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/UCM518224.pdf Accessed August 1, 2016
- 51 Zhu L, Ge G, Liu Y, He G, Liang S, Fang Z, Dong P, Cao Y, Yang L. Potent and selective inhibition of magnolol on catalytic activities of UGT1A7 and 1A9. Xenobiotica 2012; 42: 1001-1008
- 52 Zhu L, Ge G, Zhang H, Liu H, He G, Liang S, Zhang Y, Fang Z, Dong P, Finel M, Yang L. Characterization of hepatic and intestinal glucuronidation of magnolol: application of the relative activity factor approach to decipher the contributions of multiple UDP-glucuronosyltransferase isoforms. Drug Metab Dispos 2012; 40: 529-538
- 53 Jeong HU, Kong TY, Kwon SS, Hong SW, Yeon SH, Choi JH, Lee JY, Cho YY, Lee HS. Effect of honokiol on cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in human liver microsomes. Molecules 2013; 18: 10681-10693
- 54 Yang L, Zhu L, Ge G, Xiao L, Wu Y, Liang S, Cao Y, Yang L, Wang D. Species-associated differences in the inhibition of propofol glucuronidation by magnolol. J Am Assoc Lab Anim Sci 2014; 53: 408-411
- 55 Xiao L, Wu Y, Zhu LL. Tissue related differences with inhibition of magnolol on propofol glucuronidation. Chinese Pharmaceutical J 2016; 18: 1596-1599
- 56 Duan J, Xiao J, Chen Y, Han FM. Inhibition of magnolol and honokiol on cytochrome P450 enzymes in rat and human liver microsomes. Chin Herbal Med 2015; 7: 167-172
- 57 Rempel V, Fuchs A, Hinz S, Karcz T, Lehr M, Koetter U, Muller CE. Magnolia extract, magnolol, and metabolites: activation of cannabinoid CB2 receptors and blockade of the related GPR55. ACS Med Chem Lett 2013; 4: 41-45
- 58 Chen HC, Hsu HT, Weng JW, Chang YF, Hsia CY, Lee HC, Chi CW. Combined effect of honokiol and rosiglitazone on cell growth inhibition through enhanced G0/G1 phase arrest in hepatoma cells. J Chin Med Assoc 2016; 79: 415-421
- 59 Kotani H, Tanabe H, Mizukami H, Amagaya S, Inoue M. A naturally occurring rexinoid, honokiol, can serve as a regulator of various retinoid x receptor heterodimers. Biol Pharm Bull 2012; 35: 1-9
- 60 Kotani H, Tanabe H, Mizukami H, Makishima M, Inoue M. Identification of a naturally occurring rexinoid, honokiol, that activates the retinoid X receptor. J Nat Prod 2010; 73: 1332-1336
- 61 Choi SS, Cha BY, Lee YS, Yonezawa T, Teruya T, Nagai K, Woo JT. Honokiol and magnolol stimulate glucose uptake by activating PI3K-dependent Akt in L6 myotubes. Biofactors 2012; 38: 372-377
- 62 Alonso-Castro AJ, Zapata-Bustos R, Dominguez F, Garcia-Carranca A, Salazar-Olivo LA. Magnolia dealbata Zucc and its active principles honokiol and magnolol stimulate glucose uptake in murine and human adipocytes using the insulin-signaling pathway. Phytomedicine 2011; 18: 926-933
- 63 Sun J, Fu X, Liu Y, Wang Y, Huo B, Guo Y, Gao X, Li W, Hu X. Hypoglycemic effect and mechanism of honokiol on type 2 diabetic mice. Drug Des Devel Ther 2015; 9: 6327-6342
- 64 Borbath I, Horsmans Y. The role of PPARgamma in hepatocellular carcinoma. PPAR Res 2008; 2008: 209520
- 65 Thulasiraman P, Johnson AB. Regulation of Mucin 1 and multidrug resistance protein 1 by honokiol enhances the efficacy of doxorubicin-mediated growth suppression in mammary carcinoma cells. Int J Oncol 2016; 49: 479-486
- 66 Bunel V, Antoine MH, Stevigny C, Nortier J, Duez P. New in vitro insights on a cell death pathway induced by magnolol and honokiol in aristolochic acid tubulotoxicity. Food Chem Toxicol 2016; 87: 77-87
- 67 Ghys K, De Palma A, Vandevenne A, Werbrouck J, Goossens A. Magnolia officinalis bark extract, a recently identified contact allergen in ʼanti-ageingʼ cosmetics. Contact Dermatitis 2015; 73: 130-132
- 68 Kalman DS, Feldman S, Feldman R, Schwartz HI, Krieger DR, Garrison R. Effect of a proprietary magnolia and phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial. Nutr J 2008; 7: 11
- 69 Garrison R, Chambliss WG. Effect of a proprietary magnolia and phellodendron extract on weight management: a pilot, double-blind, placebo-controlled clinical trial. Altern Ther Health Med 2006; 12: 50-54
- 70 Schifano F, Guarino V, Papanti DG, Baccarin J, Orsolini L, Corkery JM. Is there a potential of misuse for Magnolia officinalis compounds/metabolites?. Hum Psychopharmacol 2017; 32: 3
- 71 Greenberg M, Urnezis P, Tian M. Compressed mints and chewing gum containing magnolia bark extract are effective against bacteria responsible for oral malodor. J Agric Food Chem 2007; 55: 9465-9469
- 72 Porciani PF, Grandini S. The effect of zinc acetate and magnolia bark extract added to chewing gum on volatile sulfur-containing compounds in the oral cavity. J Clin Dent 2012; 23: 76-79
- 73 Porciani PF, Grandini S, Chazine M. The effect of zinc lactate and magnolia bark extract added tablets on volatile sulfur-containing compounds in the oral cavity. J Clin Dent 2014; 25: 53-56
- 74 Campus G, Cagetti MG, Cocco F, Sale S, Sacco G, Strohmenger L, Lingstrom P. Effect of a sugar-free chewing gum containing magnolia bark extract on different variables related to caries and gingivitis: a randomized controlled intervention trial. Caries Res 2011; 45: 393-399
- 75 Disciplina dellʼimpiego negli integratori alimentari di sostanze e preparati vegetali. (12A07895) DOI, 2012)Z. Italian Ministry of Health. Available at: http://www.salute.gov.it/imgs/C_17_pagineAree_1268_listaFile_itemName_2_file.pdf Accessed June 18, 2018
- 76 JECFA, ECoFA. Safety evaluation of certain food additives and contaminants. In: World Health Organization. ed. WHO FOOD ADDITIVES SERIES. Geneva, Switzerland: WHO Press, World Health Organization; 2011: 64
- 77 Ministry of Health of the Peopleʼs Republic of China. Pharmacopoeia of the Peopleʼs Republic of China (English edition). Beijing: China Medical Science Press; 1988
- 78 Mohd Nor NH, Othman F, Mohd Tohit ER, Md Noor S. Medicinal herbals with antiplatelet properties benefit in coronary atherothrombotic diseases. Thrombosis 2016; 2016: 5952910
- 79 Teng CM, Ko FN, Wang JP, Lin CN, Wu TS, Chen CC, Huang TF. Antihaemostatic and antithrombotic effect of some antiplatelet agents isolated from Chinese herbs. J Pharm Pharmacol 1991; 43: 667-669
- 80 Lee TY, Chang CC, Lu WJ, Yen TL, Lin KH, Geraldine P, Li JY, Sheu JR. Honokiol as a specific collagen receptor glycoprotein VI antagonist on human platelets: functional ex vivo and in vivo studies. Sci Rep 2017; 7: 40002
- 81 Lu YC, Chen HH, Ko CH, Lin YR, Chan MH. The mechanism of honokiol-induced and magnolol-induced inhibition on muscle contraction and Ca2+ mobilization in rat uterus. Naunyn Schmiedebergs Arch Pharmacol 2003; 368: 262-269
- 82 Zhang Q, Ye X, Wang L, Peng B, Zhang Y, Bao J, Li W, Wei J, Wang A, Jin H, Chen S. Embryo-fetal development toxicity of honokiol microemulsion intravenously administered to pregnant rats. Regul Toxicol Pharmacol 2016; 74: 117-122