Abstract
Gymnopilus junonius (Fr.) P. D. Orton (Cortinariaceae) is a hallucinogenic mushroom, a well-known poisonous mushroom that is widely known as "big laughter mushroom" because it causes excessive laughter in those who consume it. Chemical investigation of G. junonius fruiting bodies was performed, resulting in the isolation and structural identification of three sesquiterpenes (1−3), including a new trichothecene sesquiterpene (2) and a new tremulane sesquiterpene (3). Compound 1 was identified from G. junonius for the first time. The chemical structures of the new compounds were established by detailed analysis of 1D and 2D (1H–1H correlated spectroscopy [COSY], heteronuclear single quantum coherence [HSQC], and heteronuclear multiple-bond coherence [HMBC]) nuclear magnetic resonance (NMR) spectra, and high-resolution mass spectrometry (HRMS). In particular, the absolute configurations of compounds 2 and 3 were unambiguously determined by quantum chemical electronic circular dichroism (ECD) calculations. The isolated compounds (1−3) were evaluated for their cytotoxic effects on human lung and prostate cancer cell lines where trichothecene sesquiterpenes (1 and 2) showed remarkable cytotoxicity similar to that of the control drug, i.e., doxorubicin. Our findings provide experimental evidence suggesting the potential anti-cancer effects of trichothecene sesquiterpenes from a poisonous mushroom.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arunachalam C, Doohan FM (2013) Trichothecene toxicity in eukaryotes: cellular and molecular mechanisms in plants and animals. Toxicol Lett 217:149–158. https://doi.org/10.1016/j.toxlet.2012.12.003
Ayer WA, Cruz ER (1993) The tremulanes, a new group of sesquiterpenes from the aspen rotting fungus Phellinus tremulae. J Org Chem 58:7529–7534. https://doi.org/10.1021/jo00078a035
Baek SC, Choi E, Eom HJ, Jo MS, Kim S, So HM, Kim SH, Kang KS, Kim KH (2018) LC/MS-based analysis of bioactive compounds from the bark of Betula platyphylla var. japonica and their effects on regulation of adipocyte and osteoblast differentiation. Nat Prod Sci 24:235–240. https://doi.org/10.20307/nps.2018.24.4.235.
Chen B, Zhang J, Han J, Zhao R, Bao L, Huang Y, Liu H (2019) Lanostane triterpenoids with glucose-uptake-stimulatory activity from peels of the cultivated edible mushroom Wolfiporia cocos. J Agric Food Chem 67:7348–7364. https://doi.org/10.1021/acs.jafc.9b02606
Choe S, In S, Jeon Y, Choi H, Kim S (2018) Identification of trichothecene-type mycotoxins in toxic mushroom Podostroma cornu-damae and biological specimens from a fatal case by LC–QTOF/MS. Forensic Sci Int 291:234–244. https://doi.org/10.1016/j.forsciint.2018.08.043
Corley DG, Rottinghaus GE, Tempesta MS (1987) Toxic trichothecenes from Fusarium sporotrichioides (MC-72083). J Org Chem 52:4405–4408. https://doi.org/10.1021/jo00228a053
Diedrich C, Grimme S (2003) Systematic investigation of modern quantum chemical methods to predict electronic circular dichroism spectra. J Phys Chem A 107:2524–2539. https://doi.org/10.1021/jp0275802
Duan XX, Qin D, Song HC, Gao TC, Zuo SH, Yan X, Wang JQ, Ding X, Di YT, Dong JY (2019) Irpexlacte A-D, four new bioactive metabolites of endophytic fungus Irpex lacteus DR10-1 from the waterlogging tolerant plant Distylium chinense. Phytochem Lett 32:151–156. https://doi.org/10.1016/j.phytol.2019.06.001
Findlay JA, He Z (1991) Minor constituents of Gymnopilus spectabilis. J Nat Prod 54:184–189. https://doi.org/10.1021/np50073a017
Garvey GS, McCormick SP, Alexander NJ, Rayment I (2009) Structural and functional characterization of TRI3 trichothecene 15-O-acetyltransferase from Fusarium sporotrichioides. Protein Sci 18:747–761. https://doi.org/10.1002/pro.80
Gonmori K, Yoshioka N (2005) Mushroom toxins. In: Suzuki O, Watanabe K (eds) Drugs and poisons in humans, a handbook of practical analysis. Springer, Berlin, pp 469–480
Graeme KA (2014) Mycetism: a review of the recent literature. J Med Toxicol 10:173–189. https://doi.org/10.1007/s13181-013-0355-2
Habrowska-Górczyńska DE, Kowalska K, Urbanek KA, Domińska K, Sakowicz A, Piastowska-Ciesielska AW (2019) Deoxynivalenol modulates the viability, ROS production and apoptosis in prostate cancer cells. Toxins 11:265. https://doi.org/10.3390/toxins11050265
Jiao Y, Kuang H, Wu J, Chen Q (2019) Polysaccharides from the edible mushroom Agaricus bitorquis (Quél.) Sacc. Chaidam show anti-hypoxia activities in pulmonary artery smooth muscle cells. Int J Mol Sci 20:637. https://doi.org/10.3390/ijms20030637
Kayano T, Kitamura N, Miyazaki S, Ichiyanagi T, Shimomura N, Shibuya I, Aimi T (2014) Gymnopilins, a product of a hallucinogenic mushroom, inhibit the nicotinic acetylcholine receptor. Toxicon 81:23–31. https://doi.org/10.1016/j.toxicon.2014.01.014
Kim KH, Choi SU, Lee KR (2012) Gymnopilin K: a new cytotoxic gymnopilin from Gymnopilus spectabilis. J Antibiot 65:135–137. https://doi.org/10.1038/ja.2011.122
Kim S, So HM, Roh HS, Kim J, Yu JS, Lee S, Seok S, Pang C, Baek KH, Kim KH (2017) Vulpinic acid contributes to the cytotoxicity of Pulveroboletus ravenelii to human cancer cells by inducing apoptosis. RSC Adv 7:35297–35304. https://doi.org/10.1039/C7RA05059C
Kim E, Kim HJ, Oh HN, Kwak AW, Kim SN, Kang BY, Cho SS, Shim JH, Yoon G (2019) Cytotoxic constituents from the roots of Asarum sieboldii in human breast cancer cells. Nat Prod Sci 25: 72–75. https://doi.org/10.20307/nps.2019.25.1.72
Lee S, Park JY, Lee D, Seok S, Kwon YJ, Jang TS, Kang KS, Kim KH (2017a) Chemical constituents from the rare mushroom Calvatia nipponica inhibit the promotion of angiogenesis in HUVECs. Bioorg Med Chem Lett 27:4122–4127. https://doi.org/10.1016/j.bmcl.2017.07.036
Lee SR, Lee D, Lee HJ, Noh HJ, Jung K, Kang KS, Kim KH (2017b) Renoprotective chemical constituents from an edible mushroom, Pleurotus cornucopiae in cisplatin-induced nephrotoxicity. Bioorg Chem 71:67–73. https://doi.org/10.1016/j.bioorg.2017.01.012
Lee S, Lee D, Lee JC, Kang KS, Ryoo R, Park HJ, Kim KH (2018a) Bioactivity-guided isolation of anti-inflammatory constituents of the rare mushroom Calvatia nipponica in LPS-stimulated RAW264.7 macrophages. Chem. Biodivers. 15:e1800203. https://doi.org/10.1002/cbdv.201800203
Lee SR, Roh HS, Lee S, Park HB, Jang TS, Ko YJ, Baek KH, Kim KH (2018b) Bioactivity-guided isolation and chemical characterization of antiproliferative constituents from Morel mushroom (Morchella esculenta) in human lung adenocarcinoma cells. J Funct Foods 40:249–260. https://doi.org/10.1016/j.jff.2017.11.012
Lee SR, Park HB, Kim KH (2018c) Highly sensitive, simple, and cost/time-effective method to determine the absolute configuration of a secondary alcohol using competing enantioselective acylation coupled with LC/MS. Anal Chem 90:13212–13216. https://doi.org/10.1021/acs.analchem.8b03385
Lee SR, Seok S, Ryoo R, Choi SU, Kim KH (2019) Macrocyclic trichothecene mycotoxins from a deadly poisonous mushroom, Podostroma cornu-damae. J Nat Prod 82:122–128. https://doi.org/10.1021/acs.jnatprod.8b00823
Li P, Tanaka S, Ichiyanagi T, Ninomiya T, Ting Y, Utami SB, Aimi T, Sshirayoshi Y, Miake J, Hisatome I (2011) Novel effects of extracts from poisonous mushrooms on expression and function of the human ether-a-go-go-related gene channel. Biol Pharm Bull 34:1474–1480. https://doi.org/10.1248/bpb.34.1474
Ngo QMT, Cao TQ, Woo MH, Min BS, Weon KY (2018) Cytotoxic triterpenoids from the fruits of Ligustrum japonicum. Nat Prod Sci 24:93–98. https://doi.org/10.20307/nps.2018.24.2.93.
Ngo QMT, Cao TQ, Woo MH, Min BS (2019) Cytotoxic lactones from the pericarps of Litsea japonica. Nat Prod Sci 25:23–27. https://doi.org/10.20307/nps.2019.25.1.23
So HM, Eom HJ, Lee D, Kim S, Kang KS, Lee IK, Baek KH, Park JY, Kim KH (2018) Bioactivity evaluations of betulin identified from the bark of Betula platyphylla var. japonica for cancer therapy. Arch Pharm Res 41:815–822. https://doi.org/10.1007/s12272-018-1064-9
Song H, Fu Y, Wan D, Xia W, Lyu F, Liu L, Shen L (2019) Mytoxin B and myrothecine A induce apoptosis in human hepatocarcinoma cell line SMMC-7721 via PI3K/Akt signaling pathway. Molecules 24:2291. https://doi.org/10.3390/molecules24122291
Suh WS, Lee SR, Kim CS, Moon E, Kim SY, Choi SU, Kang KS, Lee KR, Kim KH (2016) A new monoacylglycerol from the fruiting bodies of Gymnopilus spectabilis. J Chem Res 40:156–159. https://doi.org/10.3184/174751916X14546877525997
Tanaka M, Hashimoto K, Okuno T, Shirahama H (1993) Neurotoxic oligoisoprenoids of the hallucinogenic mushroom, Gymnopilus spectabilis. Phytochemistry 34:661–664. https://doi.org/10.1016/0031-9422(93)85335-O
Wang X, Su GY, Zhao C, Qu FZ, Wang P, Zhao YQ (2018) Anticancer activity and potential mechanisms of 1C, a ginseng saponin derivative, on prostate cancer cells. J Ginseng Res 42:133–143. https://doi.org/10.1016/j.jgr.2016.12.014
Wu X, Lin S, Zhu C, Yue Z, Yu Y, Zhao F, Liu B, Dai J, Shi J (2010) Homo- and heptanor-sterols and tremulane sesquiterpenes from cultures of Phellinus igniarius. J Nat Prod 73:1294–1300. https://doi.org/10.1021/np100216k
Wu YM, Zhou QY, Yang XQ, Luo YJ, Qian JJ, Liu SX, Yang YB, Ding ZT (2019) Induction of antiphytopathogenic metabolite and squalene production and phytotoxin elimination by adjustment of the mode of fermentation in cocultures of phytopathogenic Nigrospora oryzae and Irpex lacteus. J Agric Food Chem 67:11877–11882. https://doi.org/10.1021/acs.jafc.9b04209
Wu PF, Ding R, Tan R, Liu J, Hu EM, Li CY, Liang GY, Yi P (2020) Sesquiterpenes from cultures of the fungus Phellinus igniarius and their cytotoxicities. Fitoterapia 140:104415. https://doi.org/10.1016/j.fitote.2019.104415
Xu YC, Xie XX, Zhou ZY, Feng T, Liu JK (2018) A new monoterpene from the poisonous mushroom Trogia venenata, which has caused sudden unexpected death in Yunnan province, China. Nat Prod Res 32:2547–2552. https://doi.org/10.1080/14786419.2018.1425851
Ye W, Chen Y, Li H, Zhang W, Liu H, Sun Z, Liu T, Li S (2016) Two trichothecene mycotoxins from Myrothecium roridum induce apoptosis of HepG-2 cells via caspase activation and disruption of mitochondrial membrane potential. Molecules 21:781. https://doi.org/10.3390/molecules21060781
Yin RH, Zhao ZZ, Chen HP, Yin X, Ji X, Dong ZJ, Li ZH, Feng T, Liu JK (2014) Tremulane sesquiterpenes from cultures of the fungus Phellinus igniarius and their vascular-relaxing activities. Phytochem Lett 10:300–303. https://doi.org/10.1016/j.phytol.2014.10.019
Ying YM, Shan WG, Zhang LW, Zhan ZJ (2013) Ceriponols A-K, tremulane sesquitepenes from Ceriporia lacerate HS-ZJUT-C13A, a fungal endophyte of Huperzia serrata. Phytochemistry 95:360–367. https://doi.org/10.1016/j.phytochem.2013.07.025
Zhang G, Geng H, Zhao C, Li F, Li ZF, Lun B, Wang C, Yu H, Bie S, Li Z (2019) Chemical constituents with inhibitory activity of NO production from a wild edible mushroom, Russula vinosa Lindbl, may be its nutritional ingredients. Molecules 24:1305. https://doi.org/10.3390/molecules24071305
Acknowledgements
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2018R1A2B2006879 and 2019R1A5A2027340). This study was also supported by a biological toxicity research grant (KNA 1-3-2, 19-5) of the National Institute of Forest Science affiliated with the Korea Forest Service. We would like to thank Dr. Young Hye Kim (Korea Basic Science Institute) for the ESIMS analysis.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Authors, Jin Hee Choi and Seon-Hee Kim are employees of Sungkyun Biotech Co., Ltd. All other authors report no conflicts of interest relevant to this article.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Lee, S., Ryoo, R., Choi, J.H. et al. Trichothecene and tremulane sesquiterpenes from a hallucinogenic mushroom Gymnopilus junonius and their cytotoxicity. Arch. Pharm. Res. 43, 214–223 (2020). https://doi.org/10.1007/s12272-020-01213-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-020-01213-6