Safety and Toxicology of Magnolol and Honokiol

Reviews Safety and Toxicology of Magnolol and Honokiol Authors Andrea Sarrica1,NataljaKirika1,MargheritaRomeo2, Mario Salmona 2,LuisaDiomede2 Affiliations ABSTRACT 1 Perfetti Van Melle Spa Lainate, Milan, Italy Magnolia officinalis and Magnolia obovata bark extracts have 2 Department of Molecular Biochemistry and Pharmacology, been used for thousands of years in Chinese and Japanese tra- – “ ” IRCCS Istituto di Ricerche Farmacologiche Mario Negri, ditional medicines and are still widely employed as herbal Milan, Italy preparations for their sedative, antioxidant, anti-inflamma- tory, antibiotic, and antispastic effects. Neolignans, particu- Key words larly magnolol and honokiol, are the main substances respon- Magnolia officinalis, Magnoliaceae, toxicity, safety, magnolol, sible for the beneficial properties of the magnolia bark extract honokiol (MBE). The content of magnolol and honokiol in MBE depends on different factors, including the Magnolia plant species, the received March 23, 2018 area of origin, the part of the plant employed, and the meth- revised May 29, 2018 od used to prepare the extract. The biological and pharmaco- accepted June 6, 2018 logical activities of magnolol and honokiol have been exten- Bibliography sively investigated. Here we review the safety and toxicologi- DOI https://doi.org/10.1055/a-0642-1966 cal properties of magnolol and honokiol as pure substances or Published online June 20, 2018 | Planta Med 2018; 84: 1151– as components of concentrated MBE, including the potential 1164 © Georg Thieme Verlag KG Stuttgart · New York | side-effects in humans after oral intake. In vitro and in vivo ISSN 0032‑0943 genotoxicity studies indicated that concentrated MBE has no mutagenic and genotoxic potential, while a subchronic study Correspondence performed according to OECD (Organisation for Economic Dr. Luisa Diomede Co-operation and Development) guidelines established a no Department of Molecular Biochemistry and Pharmacology, adverse effect level for concentrated MBE > 240 mg/kg IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri” b.w/d. Similar to other dietary polyphenols, magnolol and Via G. La Masa 19, 20156 Milano, Italy honokiol are subject to glucuronidation, and despite a rela- Phone: + 3902390141, Fax: + 390239014744 tively quick clearance, an interaction with pharmaceutical ac- [email protected] tive principles or other herbal constituents cannot be ex- cluded. However, intervention trials employing concentrated Supporting information available online at MBE for up to 1 y did not report adverse effects. In conclusion, http://www.thieme-connect.de/products over the recent years different food safety authorities eval- uated magnolol and honokiol and considered them safe. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Introduction ing M. officinalis bark extract have recently appeared on the mar- ket, although their anti-aging effects have not been scientifically MBE has been used for thousands of years in traditional Chinese, proved. For its digestive and rebalancing activity on the oral Japanese, and Korean medicine and has recently been introduced microbiome, various different European national institutions have as an active ingredient in food supplements and cosmetics. included M. officinalis (flos, cortex) in lists of herbal preparations Among the different magnolia species, Magnolia officinalis Rehder suitable for inclusion in food supplements [3]. & E. H.Wilson (Magnoliaceae, commonly called Hou Po magnolia Neolignans, particularly magnolol and honokiol (▶ Fig. 1), are or magnolia bark) and Magnolia obovata Thunb are the ones most reported to be the compounds mainly responsible for MBEʼs ben- often used for these purposes. Their bark and flower extracts are eficial properties, and their biological and pharmacological activ- used alone or combined with other herbal-derived compounds as ities have been extensively investigated [2, 4–6]. The aim of this remedies for gastrointestinal disorders, anxiety, and allergies [1, review is to have a critical look to the safety and toxicological 2]. The other pharmacological activities described for MBE and properties of magnolol and honokiol, as pure substances or as its major constituents include sedative, antioxidant, anti-inflam- components of concentrated MBE containing more than 90% of matory, antibiotic, and antispastic effects [3]. Cosmetics contain- total neolignans, on the basis of a critical, systematic analysis of Sarrica A et al. Safety and Toxicology… Planta Med 2018; 84: 1151–1164 1151 Reviews ABBREVIATIONS CYP cytochrome P450 CYP1A cytochrome P450, family 1, subfamily A, polypeptide HIM human intestinal microsomes HLM human liver microsomes MBE magnolia bark extract NOAEL no adverse effect level ▶ Fig. 1 Chemical structures of magnolol and honokiol. PICOS patient, problem or population intervention, comparison, control or comparator, outcome with added qualitative search terms PPARγ peroxisome proliferator-activated receptor gamma PRISMA preferred reporting items for systematic reviews and meta-analyses RTECS Registry of Toxic Effects of Chemical Substances RXR retinoic X receptor SULT sulfotransferase T1/2 half-life UDP uridine diphosphate UGT glucuronosyltransferase the literature. To retrieve all the pertinent toxicology evidence, we applied the PICOS conceptual framework and the applicable fea- tures of the PRISMA statement [7,8] to a structured literature search using a multidatabase platform. The search was done on ▶ Fig. 2 Flow diagram depicting the systematic review strategy. May 25, 2017, with a global geographical coverage and time lim- its from the year 1910 to the date of the search. It involved the following databases: AdisInsight Safety, Allied & Complementary Medicine, Biosis Toxicology, Embase, Global Health, International ▶ Pharmaceutical Abstracts, Medline, RTECS. After applying prese- Table 1 Neolignans content in crude ethanolic or methanolic MBEs from different magnolia species. lected inclusion and exclusion criteria, three authors reviewed each article for inclusion or exclusion to reach consensus, and Neolignans Neolignans contenta (% of total weight) 44 original articles were deemed pertinent for inclusion in the sys- M. obovata M. officinalis tematic review (▶ Fig. 2). Additional details on the bibliographic Magnolol 0.78–7.65 1.00–1.25 strategy are provided as Supporting Information. Honokiol 0.55–1.25 0.17–1.81 4-O-methyl-honokiol 0.01–0.21 0.0003–1.24 Magnolol and Honokiol Content in MBE Obovatol 0.01–0.33 not detectable This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. The content of magnolol and honokiol in the magnolia crude ex- a Data represent the minimum and maximal values, as reported by Lee tract is a key feature of the quality of MBE and can vary by more et al., 2011 [2]. than 10 times depending on various factors, including the Magno- lia species (officinalis or obovata) employed for the preparation, the part of the plant used, and the method of extraction [2,9– 15]. Similarly, the content of the other lignans such as 4-O-meth- kiol concentrations in the bark varying by a factor of about 10 yl-honokiol and obovatol can vary; this last may even be absent in when samples from the West Hubei were compared to samples a M. officinalis extract (▶ Table 1). The area of origin can also from Mount Lushan (▶ Fig. 3) [11]. The concentrations of magno- markedly affect the phenolic content of the extract, such as quer- lol and honokiol, and their ratios, in extracts from the trunks of cetin and cyaniding, reflecting differences in climatic conditions Magnolia officinalis var. biloba trees grown in the same Zhejiang and environmental biodiversity in the different regions of China region also differ (▶ Table 2). The quality of the extract is also in- where magnolia trees are grown (▶ Fig. 3). Plantations of M. offi- fluenced by the altitude of the cultivar (▶ Fig. 3) and by the part of cinalis of the same age but from different Chinese regions, all at the plant collected to prepare the bark: trunk, branches, or root an altitude of around 1000 meters, had total magnolol plus hono- [2, 10, 11, 16]. Roots seem to contain the highest concentrations 1152 Sarrica A et al. Safety and Toxicology … Planta Med 2018; 84: 1151–1164 of magnolol and honokiol (87–96 mg/g of bark for each neolig- nan) (▶ Table 2) [10,16]. Considering all the influencing factors, the concentrations of the two neolignans in the bark can differ even several hundred-fold, ranging for honokiol from 0.07 mg/g to 96.51 mg/g, and for magnolol from 0.05 mg/g to 91.91 mg/g [16]. Consequently, the content of total neolignans in the extracts may be different, too, as well as the ratio between the magnolol and honokiol concentrations, which can range from as little as 0.42 to as much as 12 (▶ Table 2). The age of the bark influences the content of neolignans, too. The percentages of magnolol and honokiol in the extract prepared from the trunk of a M. officinalis tree change with its age, peaking when the plant is 27 y old [17]. Last but not least, different methods can be employed for the extraction of neolignans from ground dried magnolia bark. These are mainly organic and/or aqueous extractions, affecting the re- covery of honokiol and magnolol. Sonication, agitation, macera- tion, or supercritical extraction at variable temperatures for different times (from a few minutes up to 24 h) may be employed to optimize the extraction

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