Preclinical study of safety of Dendropanax morbifera Leveille leaf extract: General and genetic toxicology

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Abstract

Ethnopharmacology relevance

Dendropanax morbifera Leveille (DM) has been used in traditional medicines for infectious and skin diseases, and dysmenorrhea. It exhibits a diverse therapeutic potential including anti-cancer, anti-thrombotic, anti-diabetic, anti-oxidant, and anti-inflammatory activities.

Aim of the study

Despite promising health benefits of DM, knowledge of its potential adverse effects is very limited. The current study focused on the investigation of subchronic toxicity and genotoxicity of extract obtained from DM according to the test guidelines published by the Organization for Economic Cooperation and Development.

Materials and methods

We conducted a toxicological evaluation of DM extracts using 14-day repeated-dose toxicity study and 13-week repeated-dose toxicity study in Sprague-Dawley rats administered orally at doses of 500, 1000, or 2000 mg/kg/day. The clastogenicity of DM extract was also evaluated by in vitro chromosome aberration assay and in vivo micronucleus assay.

Results

Assessment of subchronic toxicity of DM extract by oral administration in rats revealed unremarkable treatment-related findings with respect to food/water consumption, body weight, mortality, urinalysis, hematology, serum biochemistry, necropsy, organ weight and histopathology at doses of 500, 1000, and 2000 mg/kg. Accordingly, the level of no-observed-adverse-effect for DM extract in 13-week subchronic toxicity study was considered to be 2000 mg/kg/day in rats. The data observed from in vitro chromosome aberration assay and in vivo micronucleus assay exclude any clastogenicity of DM extract.

Conclusion

The results suggest that the oral consumption of DM extract has no adverse effects in humans and represents a safe traditional medicine.

Introduction

Dendropanax morbifera Leveille (DM) is a subtropical broad-leaved evergreen tree belonging to the family Araliaceae. It is known as Hwangchil in Korea, and is an endemic species found in the southwestern region of South Korea, mainly in the Jeju Island (Han et al., 1998). In traditional herbal medicine in Korea, DM is believed to improve blood circulation in Donguibogam (written in the 17th century, Korean) (Choi et al., 2015). Several studies have extensively demonstrated the potential therapeutic benefits of DM such as anti-cancer, anti-thrombotic, anti-diabetic, anti-oxidant, and anti-inflammatory activities (Moon, 2011; Yu et al., 2012a; Hyun et al., 2013; Lee et al., 2013; Kim et al., 2014, 2015; Akram et al., 2016). DM extract has also been reported to display antibiotic activity against Staphylococcus aureus (Lee et al., 1998). Another study performed by the Korean Ministry of Science and Technology (Im et al., 1996) investigated the antibacterial and antifungal effects of the DM extracts.

In recent years, traditional herbal products have gained popularity worldwide because of easy access and convenience (Jiang, 2005; Liu et al., 2008). In particular, they are effective therapeutic targets for research free from adverse side effects (Markman, 2002; Shin et al., 2013). In fact, several lines of evidence suggest the absence of adverse reactions of herbal medicines when administered orally (Ito et al., 2014; Lee et al., 2015a; Yun et al., 2015a). However, the genotoxic or systemic toxicity potentials associated with hepatic/renal dysfunction of a few natural products have been established by our group (Che et al., 2014, 2015; Yun et al., 2015b, 2015c). These studies emphasized the importance of comprehensive safety assessment even for beneficial herbal medicines available on the traditional market. Nonetheless, along with prejudice against the safety of herbal medicine, no safety data regarding potential hazard involved in the DM extract has been assessed according to the test guidelines published by the Organization for Economic Cooperation and Development (OECD). The present studies represent a comprehensive investigation into the subchronic oral toxicity and the clastogenicity profile of the extract derived from the leaves of DM.

Section snippets

Test substance and animals

The leaves of wild DM were collected from Jangheung in Korea in October 2011 and authenticated by Dr. Kim in the field of herbal medicine at the Jeollanamdo Institute of Natural Resources Research (Jangheung, Korea). Voucher specimen (JINR2003) has been deposited at the Jeollanamdo Institute of Natural Resources Research in Korea. Extracts were obtained from the leaves of DM using 20 vol of distilled water (DW) at 100 °C for 4 h. The extracted solution was filtered, concentrated using an

14-Day repeat-dose oral toxicity study

Several phenolic compounds, including rutin and quercetin, have been identified as the major active components of DM extract (Hyun et al., 2015). The amounts of rutin (10.52 mg/g) and quercetin (2.99 mg/g) were estimated in the DM extract used in the present study (data not shown).

No dose-related animal deaths following the administration of DM extract were observed until the scheduled termination during the experimental phase of the 14-day repeat-dose oral toxicity study for the selection of

Discussion

In traditional systems of medicine, various parts (stems, roots, leaves, and seeds) of DM have been used as a form of alternative medicine for several conditions including headache, infectious diseases, skin diseases, and dysmenorrhea (Bae, 2000). Similarly, several attempts were made to exploit the DM-derived substances for their hepatoprotective (Bae et al., 2015), anti-oxidant (Kim et al., 2015), anticomplement (Park et al., 2004; Chung et al., 2011), anti-diabetic (Moon, 2011),

Conclusion

The results demonstrated that the DM extract did not exert any clastogenicity based on the in vitro chromosome aberration assay and in vivo micronucleus assay. More importantly, a 13-week repeated oral administration of the DM extract had no dose-related adverse effects in rats. Under our experimental conditions, the no-observed-adverse-effect-level of the DM extract was >2000 mg/kg/day in both male and female rats and no apparent target organ damage was identified when administered

Conflicts of interest

The authors declare no conflict of interests.

Author contributions

J.W.Y. contributed to the analyzing the data and wrote the manuscript. S.H.K., Y.S.K., J.R.Y., E.Y.C., J.H.Y., and E.K. extracted extracts and performed the biological experiments. H.C.K. participated in the design of the study and provided technical advices. J.J.J. conducted pathological analysis. J.S.P. contributed to the drafting the manuscript. J.H.C. and B.C.K. participated in the design of the study, in discussions and reviewed the manuscript. All authors read and approved the final

Acknowledgements

This work was supported by the Ministry of Knowledge Economy for the Regional Innovation System program in 2011 (No. B0012328, 00000-63206-A000900032) and the Catholic University of Korea, Research Fund, 2018.

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