Research progress on the toxicity of Asari Radix et Rhizoma

Xin Li, Ranyun Chen, Shuni Duan, Yijie Li, Huiping Zhou, Runping Liu, Rong Sun

PDF(1138 KB)
PDF(1138 KB)
Acupuncture and Herbal Medicine ›› 2024, Vol. 4 ›› Issue (2) : 197-208. DOI: 10.1097/HM9.0000000000000114
Review Articles
research-article

Research progress on the toxicity of Asari Radix et Rhizoma

Author information +
History +

Abstract

Asari Radix et Rhizoma (ARR), also known as Xixin, has been broadly used as a traditional herbal medicine in East Asia and is an important component of classic prescriptions, including Mahuang Fuzi Xixin decoction. It was initially classified as a “top grade” herb in ancient Chinese Pharmacopeia, Shennong’s Materia Medica. Volatile oils, lignans, fatty acids, flavonoids, and nitrogen-containing compounds are the main ARR components. Previous pharmacological studies have shown that ARR exerts beneficial effects in humans for treating headaches, toothaches, and several inflammatory diseases by dispelling wind and cold, alleviating pain, and eliminating phlegm. However, “the dosage of ARR should not exceed one coin (approximately 3.75 grams),” as stated in Shizhen Li’s Compendium of Materia, which emphasized the considerable ARR toxicity and significantly constrained its clinical application. This review aimed to consolidate recent advancements in the understanding of the toxic ARR components. Additionally, we provide an overview of the hepatotoxicity, genotoxicity, neurotoxicity, and pulmonary toxicity of ARR and discuss the underlying molecular mechanisms. This study reviews the limitations of current studies and enhances our understanding of the toxic effects of ARR from the perspective of its toxic components and mechanisms, thereby providing a theoretical basis for the rational clinical practice of ARR-based medications.

Keywords

Asari Radix et Rhizoma / Powder / Toxicity / Volatile oil / Xixin

Cite this article

Download citation ▾
Xin Li, Ranyun Chen, Shuni Duan, Yijie Li, Huiping Zhou, Runping Liu, Rong Sun. Research progress on the toxicity of Asari Radix et Rhizoma. Acupuncture and Herbal Medicine, 2024, 4(2): 197‒208 https://doi.org/10.1097/HM9.0000000000000114

References

[[1]]
Yang L, Huang Y, Shen T. Talking again about “the dosage of asarum should not exceed one penny”. Chin J Tradit Chin Med. 2024;39(1):106-109.
[[2]]
Wang Q, Zhou Z, Huang F, et al. Academic inheritance and innovation of traditional Chinese medicine based on asarum dose research. Shizhen Tradit Chin Med. 2016;27(7):1687-1688.
[[3]]
Wu H, Wen X, Yan P, et al. Research progress on the chemical composition and pharmacological effects of Asarum. Chin J Exp Prescriptions. 2021;27(4):186-195.
[[4]]
Liu F, Zhang R, Zhou C. A case of heart failure after overdose of asarum. Chin J Tradit Chin Med. 1995;20(7):440.
[[5]]
Chen X, Wang S. A case of arrhythmia caused by excessive asarum. Jiangsu Tradit Chin Med. 1994;15(1):10.
[[6]]
Long Y’e, Ye S, Chen X. One case of successful rescue of severe acute asarum poisoning. Shaanxi Tradit Chin Med. 1999;20(6):282.
[[7]]
Michl J, Ingrouille MJ, Simmonds MSJ, et al. Naturally occurring aristolochic acid analogues and their toxicities. Nat Prod Rep. 2014;31(5):676-693.
[[8]]
Kumar V, Poonam, Prasad AK, et al. Naturally occurring aristolactams, aristolochic acids and dioxoaporphines and their biological activities. Nat Prod Rep. 2003;20(6):565-583.
[[9]]
Zhang Z, Shao Z, Hao L, et al. Determination of aristolochic acid I content in different parts of Asarum by HPLC-UV method. Northeast Agric Sci. 2024;49(1):105-107.
[[10]]
Wang W, Jia X, Gao M, et al. Analysis of volatile components of Asarum by steam distillation and headspace sampling GC-MS. Tianjin Tradit Chin Med. 2021;38(5):654-658.
[[11]]
Li J, Yan W, Cui E, et al. GC-MS analysis of volatile oil components of Asarum from different origins. Shizhen Tradit Chin Med. 2019;30(1):188-190.
[[12]]
Jeng KCG, Hou RC, Wang JC, et al. Sesamin inhibits lipopolysaccharide-induced cytokine production by suppression of p38 mitogen-activated protein kinase and nuclear factor-κB. Immunol Lett. 2005;97(1):101-106.
[[13]]
Hua X, Liu C, He M, et al. Research progress on the chemical components and pharmacological effects of Asarum and its quality marker (Q-Marker) prediction analysis. Chin Herb Med. 2023;54(12):4019-4035.
[[14]]
Dong Y, Yu H, Wang C, et al. Research on the chemical composition of Asarum root. Tianjin Tradit Chin Med. 2017;34(12):845-848.
[[15]]
Zhang C, Yu J, Liu G, et al. Distribution and content analysis of 3 kinds of aristolochic acids and 2 kinds of aristolochlactams in different parts of Asarum asarum, Asarum sinensis and Asarum Hancheng. World Sci Technol Mod Tradit Chin Med. 2019;21(7):1295-1305.
[[16]]
Liu D, Liu C. Research on the volatile oil of Asarum cultivated in different origins. Chin J Exp Prescriptions. 2010;16(9):79-82.
[[17]]
Nie A, Bian M, Zhu C. Effects of different doses of asarum decoction on liver, kidney, and lung toxicity in rats. Tradit Chin Med Inf. 2023;40(7):53-57.
[[18]]
Zhou Z, Yang W, Chen Z, et al. Pathological effects of Xixin powder on important organs in mice. J Tradit Chin Med. 2004;22(5):847-885.
[[19]]
Li J, Yang W, Zhou Z, et al. Study on the long-term toxicity of asarum—the effects of long-term and large-scale administration of asarum on liver tissue morphology and function in rats. J Hubei Coll Tradit Chin Med. 2008;10(1):5-7.
[[20]]
Wu JZ, Ma Z, Zhang YH, et al. Precise subcellular organelle-targeted analyses of the hepatotoxicity of rhubarb. Acupunct Herb Med. 2024;4(2):243-256.
[[21]]
Liu Y. Research on the “component-toxicity/effect” correlation rules of Asarum volatile oil and aging and attenuation of toxicity [D] Jiangxi University of Traditional Chinese Medicine; 2023.
[[22]]
Sudheer AR, Muthukumaran S, Devipriya N, et al. Influence of ferulic acid on nicotine-induced lipid peroxidation, DNA damage and inflammation in experimental rats as compared to N-acetylcysteine. Toxicology. 2008;243(3):317-329.
[[23]]
Wang K, Liu H, Sun W, et al. Eucalyptol alleviates avermectin exposure-induced apoptosis and necroptosis of grass carp hepatocytes by regulating ROS/NLRP3 axis. Aquat Toxicol. 2023;264:106739.
[[24]]
Pham TH, Lee GH, Jin SW, et al. Sesamin ameliorates lipotoxicity and lipid accumulation through the activation of the estrogen receptor alpha signaling pathway. Biochem Pharmacol. 2023;216:115768.
[[25]]
Du H, Tong S, Kuang G, et al. Sesamin protects against APAP-induced acute liver injury by inhibiting oxidative stress and inflammatory response via deactivation of HMGB1/TLR4/NFκB signal in mice. J Immunol Res. 2023;2023:1116841.
[[26]]
Kim HY, Park J, Lee KH, et al. Ferulic acid protects against carbon tetrachloride-induced liver injury in mice. Toxicology. 2011;282(3):104-111.
[[27]]
Cao SA. Research on the hepatotoxicity mechanism of Xixin Powder based on metabolomics and transcriptomics[D] Hubei University of Traditional Chinese Medicine; 2020.
[[28]]
Cao S, Han L, Li Y, et al. Integrative transcriptomics and metabolomics analyses provide hepatotoxicity mechanisms of asarum. Exp Ther Med. 2020;20(2):1359-1370.
[[29]]
Abdo KM, Cunningham ML, Snell ML, et al. 14-Week toxicity and cell proliferation of methyleugenol administered by gavage to F344 rats and B6C3F1 mice. Food Chem Toxicol. 2001;39(4):303-316.
[[30]]
López ML, Hernández A, Chamorro G, et al. alpha-Asarone toxicity in long-term cultures of adult rat hepatocytes. Planta Med. 1993;59(2):115-120.
[[31]]
Polasek TM, Miners JO. In vitro approaches to investigate mechanism-based inactivation of CYP enzymes. Expert Opin Drug Metab Toxicol. 2007;3(3):321-329.
[[32]]
Masubuchi Y, Nakano T, Ose A, et al. Differential selectivity in carbamazepine-induced inactivation of cytochrome P450 enzymes in rat and human liver. Arch Toxicol. 2001;75(9):538-543.
[[33]]
Fontana E, Dansette PM, Poli SM. Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity. Curr Drug Metab. 2005;6(5):413-454.
[[34]]
Ueng YF, Hsieh CH, Don MJ. Inhibition of human cytochrome P450 enzymes by the natural hepatotoxin safrole. Food Chem Toxicol. 2005;43(5):707-712.
[[35]]
Yang AH, Zhang L, Zhi DX, et al. Identification and analysis of the reactive metabolites related to the hepatotoxicity of safrole. Xenobiotica. 2018;48(11):1164-1172.
[[36]]
Hu L, Wu F, He J, et al. Cytotoxicity of safrole in HepaRG cells: studies on the role of CYP1A2-mediated ortho-quinone metabolic activation. Xenobiotica. 2019;49(12):1504-1515.
[[37]]
Yang AH, He X, Chen JX, et al. Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2. Chem Biol Interact. 2015;237:133-140.
[[38]]
Yu Q, Chen Y, Ju H, et al. Molecular docking analysis of volatile oil components of Asarum and CYP1A2 enzyme. Chin J Exp Prescriptions. 2020;26(9):202-207.
[[39]]
Feng Y, Wang H, Wang Q, et al. Chemical interaction of protein cysteine residues with reactive metabolites of methyleugenol. Chem Res Toxicol. 2017;30(2):564-573.
[[40]]
Liu TY, Chen CC, Chen CL, et al. Safrole-induced oxidative damage in the liver of Sprague-Dawley rats. Food Chem Toxicol. 1999;37(7):697-702.
[[41]]
Nakagawa Y, Suzuki T, Nakajima K, et al. Biotransformation and cytotoxic effects of hydroxychavicol, an intermediate of safrole metabolism, in isolated rat hepatocytes. Chem Biol Interact. 2009;180(1):89-97.
[[42]]
Patel DN, Ho HK, Tan LL, et al. Hepatotoxic potential of asarones: in vitro evaluation of hepatotoxicity and quantitative determination in herbal products. Front Pharmacol. 2015;6:25.
[[43]]
Zhao G, Ma Y, Wang X, et al. Configurational alteration results in change in hepatotoxicity of asarone. J Agric Food Chem. 2023;71(1):884-894.
[[44]]
Song J, Li J, Yang N, et al. Experimental study on the genotoxicity of the traditional Chinese medicine Asarum. Chin Pharmacovigilance. 2010;7(5):262-264.
[[45]]
Rietjens IMCM, Boersma MG, Van der Woude H, et al. Flavonoids and alkenylbenzenes: mechanisms of mutagenic action and carcinogenic risk. Mutat Res. 2005;574(1-2):124-138.
[[46]]
Chen XW, Serag ES, Sneed KB, et al. Herbal bioactivation, molecular targets and the toxicity relevance. Chem Biol Interact. 2011;192(3):161-176.
[[47]]
Zhou GD, Moorthy B, Bi J, et al. DNA adducts from alkoxyallylbenzene herb and spice constituents in cultured human (HepG2) cells. Environ Mol Mutagen. 2007;48(9):715-721.
[[48]]
Kobets T, Duan JD, Brunnemann KD, et al. Structure-activity relationships for DNA damage by alkenylbenzenes in Turkey egg fetal liver. Toxicol Sci. 2016;150(2):301-311.
[[49]]
Kobets T, Cartus AT, Fuhlbrueck JA, et al. Assessment and characterization of DNA adducts produced by alkenylbenzenes in fetal turkey and chicken livers. Food Chem Toxicol. 2019;129:424-433.
[[50]]
Boberg EW, Miller EC, Miller JA, et al. Strong evidence from studies with brachymorphic mice and pentachlorophenol that 1’-sulfoöxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1’-hydroxysafrole in mouse liver. Cancer Res. 1983;43(11):5163-5173.
[[51]]
Martati E, Boonpawa R, Van den Berg JHJ, et al. Malabaricone C-containing mace extract inhibits safrole bioactivation and DNA adduct formation both in vitro and in vivo. Food Chem Toxicol. 2014;66:373-384.
[[52]]
Zhou SF, Xue CC, Yu XQ, et al. Metabolic activation of herbal and dietary constituents and its clinical and toxicological implications: an update. Curr Drug Metab. 2007;8(6):526-553.
[[53]]
Shen LC, Chiang SY, Lin MH, et al. In vivo formation of N7-guanine DNA adduct by safrole 2’,3’-oxide in mice. Toxicol Lett. 2012;213(3):309-315.
[[54]]
Wu KY, Wei YT, Luo YS, et al. Dose-response formation of N7-(3-benzo[1,3]dioxol-5-yl-2-hydroxypropyl)guanine in liver and urine correlates with micronucleated reticulocyte frequencies in mice administered safrole oxide. Food Chem Toxicol. 2023;181:114056.
[[55]]
Cartus AT, Herrmann K, Weishaupt LW, et al. Metabolism of methyleugenol in liver microsomes and primary hepatocytes: pattern of metabolites, cytotoxicity, and DNA-adduct formation. Toxicol Sci. 2012;129(1):21-34.
[[56]]
Tremmel R, Herrmann K, Engst W, et al. Methyleugenol DNA adducts in human liver are associated with SULT1A1 copy number variations and expression levels. Arch Toxicol. 2017;91(10):3329-3339.
[[57]]
Herrmann K, Engst W, Meinl W, et al. Formation of hepatic DNA adducts by methyleugenol in mouse models: drastic decrease by Sult1a1 knockout and strong increase by transgenic human SULT1A1/2. Carcinogenesis. 2014;35(4):935-941.
[[58]]
Carlsson MJ, Vollmer AS, Demuth P, et al. p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol. Cell Death Dis. 2022;13(11):1009.
[[59]]
Bergau N, Herfurth UM, Sachse B, et al. Bioactivation of estragole and anethole leads to common adducts in DNA and hemoglobin. Food Chem Toxicol. 2021;153:112253.
[[60]]
Deshmukh PU, Lad SB, Sudarsan A, et al. Human translesion synthesis polymerases polκ and polη perform error-free replication across N2-dG methyleugenol and estragole DNA adducts. Biochemistry. 2023;62(16):2391-2406.
[[61]]
Paini A, Punt A, Scholz G, et al. In vivo validation of DNA adduct formation by estragole in rats predicted by physiologically based biodynamic modelling. Mutagenesis. 2012;27(6):653-663.
[[62]]
Suzuki Y, Umemura T, Ishii Y, et al. Possible involvement of sulfotransferase 1A1 in estragole-induced DNA modification and carcinogenesis in the livers of female mice. Mutat Res. 2012;749(1-2):23-28.
[[63]]
Probert PM, Palmer JM, Alhusainy W, et al. Progenitor-derived hepatocyte-like (B-13/H) cells metabolise 1’-hydroxyestragole to a genotoxic species via a SULT2B1-dependent mechanism. Toxicol Lett. 2016;243:98-110.
[[64]]
Uebel T, Wilken M, Vu Chi H, et al. In vitro combinatory cytotoxicity of hepatocarcinogenic asarone isomers and flavonoids. Toxicol In Vitro. 2019;60:19-26.
[[65]]
Hermes L, Haupenthal S, Uebel T, et al. DNA double strand break repair as cellular response to genotoxic asarone isomers considering phase I metabolism. Food Chem Toxicol. 2020;142:111484.
[[66]]
Stegmüller S, Schrenk D, Cartus AT. Formation and fate of DNA adducts of alpha- and beta-asarone in rat hepatocytes. Food Chem Toxicol. 2018;116:138-146.
[[67]]
Uebel T, Hermes L, Haupenthal S, et al. α-Asarone, β-asarone, and γ-asarone: current status of toxicological evaluation. J Appl Toxicol. 2021;41(8):1166-1179.
[[68]]
Hermes L, Römermann J, Cramer B, et al. Quantitative analysis of β-asarone derivatives in Acorus calamus and herbal food products by HPLC-MS/MS. J Agric Food Chem. 2021;69(2):776-782.
[[69]]
Ishii Y, Shi L, Takasu S, et al. A 13-week comprehensive toxicity study with adductome analysis demonstrates the toxicity, genotoxicity, and carcinogenicity of the natural flavoring agent elemicin. Food Chem Toxicol. 2023;179:113965.
[[70]]
Bolton JL, Acay NM, Vukomanovic V. Evidence that 4-allyl-o-quinones spontaneously rearrange to their more electrophilic quinone methides: potential bioactivation mechanism for the hepatocarcinogen safrole. Chem Res Toxicol. 1994;7(3):443-450.
[[71]]
Ding W, Levy DD, Bishop ME, et al. In vivo genotoxicity of estragole in male F344 rats. Environ Mol Mutagen. 2015;56(4):356-365.
[[72]]
Ding W, Levy DD, Bishop ME, et al. Methyleugenol genotoxicity in the Fischer 344 rat using the comet assay and pathway-focused gene expression profiling. Toxicol Sci. 2011;123(1):103-112.
[[73]]
Wang X, Ran G, Liao Y, et al. Formation of RNA adducts resulting from metabolic activation of spice ingredient safrole mediated by P450 enzymes and sulfotransferases. Food Chem Toxicol. 2023;174:113688.
[[74]]
Wang Y, Guo S, Cao J, et al. Toxic and repellent effects of volatile phenylpropenes from Asarum heterotropoides on Lasioderma serricorne and Liposcelis bostrychophila. Molecules. 2018;23(9):2131.
[[75]]
Liu Y, Wang F, Guo H, et al. Effect of molecular distillation on the anti-inflammatory activity and neurotoxicity of Asarum essential oil. Front Pharmacol. 2023;14:1196137.
[[76]]
Guo KF, Dai M, Liu YM, et al. Acute administration of methyleugenol impairs hippocampus-dependent contextual fear memory and increases anxiety-like behavior in mice. J Agric Food Chem. 2020;68(28):7490-7497.
[[77]]
Zhou Z, Li J, Chen Z, et al. Effects of Asari powder on respiratory movement and phrenic nerve electrical activity of rabbits. Hubei J Tradit Chin Med. 2005;27(4):3-5.
[[78]]
Yang W, Zhou Z, Chen Z, et al. Effects of Asarum medicated serum on INa of DRG neurons in SD rats. J Guangxi Coll Tradit Chin Med. 2006;9(4):3-7.
[[79]]
Yang W, Wang Q, Zhou Z, et al. Effects of Asarum medicated serum on IK of DRG neurons in SD rats. J Hubei Coll Tradit Chin Med. 2009;11(5):6-9.
[[80]]
Qiu D, Hou L, Chen Y, et al. Beta-asarone inhibits synaptic inputs to airway preganglionic parasympathetic motoneurons. Respir Physiol Neurobiol. 2011;177(3):313-319.
[[81]]
Cai Q, Zhou Z, Chen Z, et al. Effects of long-term toxicity of asarum on lung tissue morphology and arterial blood gas in rats. Hubei J Tradit Chin Med. 2007;29(4):3-5.
[[82]]
Li Y, Han L, Huang C, et al. New contributions to asarum powder on immunology related toxicity effects in lung. Evid Based Complement Alternat Med. 2018;2018:1054032.
[[83]]
Nielsen GD, Larsen ST, Hougaard KS, et al.Mechanisms of acute inhalation effects of(+) and 2005;96(6):420-428.
[[84]]
Liu M, Wang L, Meng J, et al. Chemical composition, pharmacological and toxicological research progress of Asarum. Chin J Exp Tradit Med Formulae. 2023;29(10):224-234.
[[85]]
Chen H, Tong Y. On Zhang Zhongjing’s rules for using Asarum. J Shanghai Univ Tradit Chin Med. 2007;21(3):12-14.
[[86]]
Chang Z. Internal dosage and toxicity of Asarum. Chin J Tradit Chin Med. 2008;33(6):721-726.
[[87]]
Huang J, Yi J, Liu Y, et al. Study on the changes of methyl eugenol, safrole and asarin during the decoction of Asarum. Chin Patent Med. 2012;34(10):1971-1974.
[[88]]
Wang X, Li L, Zhang Y, et al. Pharmacodynamics and toxicology studies of Asarum before and after processing. China Med Her. 2015;12(22):36-39.

RIGHTS & PERMISSIONS

2024 Acupuncture and Herbal Medicine
PDF(1138 KB)

Accesses

Citations

Detail

Sections
Recommended

/