Review Article

Toxicity Assessment of Herbal Medicine Using Zebrafish Embryos: A Systematic Review

Table 3

Evaluation of the toxicity of phytochemical constituents of herbal medicine using the Zebrafish embryotoxicity model.

No.Name of constituentPhytochemical groupHerbal plant and partMedicinal valueToxic effectsReferenceToxicity compared with other assays
Survival/mortality rateTeratogenic and other toxic effects

1Five anthraquinones, seven anthrones, and two naphtholsPolygonum multiflorum Thunb., whole plantAntiageing, antihyperlipidaemia, antioxidant, anti-inflammatory, anticancer, hepatoprotective, and immunomodulating effectsLD50 values have been calculated for each compound at 48, 72 and 96 hpfNotochord malformations were observed[34]Not compared
2MatrineAlkaloidsKushen in traditional Chinese medicine root of Sophora flavescensPossessing a variety of pharmacological effects such as anti-inflammation, antivirus, antitumour, and antiarrhythmic activitiesEC50 and LC50 values at 145 and 240 mg/LOedema, growth retardation has been observed after 48 hrs concentrations below those causing lethality and malformations, indicating a neurotoxic potential of both drugs[35]Not compared
3Sophocarpine.EC50 and LC50 values 87.1 and 166 mg/L
4CelastrolTerpenoidThunder God vine Tripterygium wilfordii Hook FAntioxidant and anti-inflammatory activities, neurodegenerative diseases and anticancerDose-dependent and the LC50 values of celastrol on embryos were approximately 1.40 μMSeveral developmental abnormalities, including no blood flow, oedema in pericardial sac, and tail malformation were reported in embryos EC50 for tail malformation was 0.66 μM at 72 hpf[36]Not compared
5EmodinAn anthraquinone derivativeRhubarb root and bark of many plants of the genus Rhamnus.Antidiabetic, antinociception, anticancer and cholesterol reduction potentialDose-related increase in mortality, with significant death of embryos at 0.25 μg/mL. The LD50 value (at 72 hpf) −0.20 μg/mLOedema, crooked trunk, and abnormal morphogenesis of some organs, such as statolith, swimming bladder, and yolk syncytium were reported in embryo treated with 0.1–1.5 μg/mL emodin[37]Not compared
6Cannabidiol (CBD)CannabisCannabis sativa whole plantNeuropsychiatric disordersCBD all concentrations did not show significant morphological demormaties.
300 μg/L have significantly delayed the hatching of the embryo
Embryos exposed to CBD 20–300 μg/L were 1.4 up to 1.7-fold more active when compared with the control. But difference in acetylcholinesterase[38]Not compared
7Aristolochic acid (AA)Aristolochia or Asarum.Arthritis, gout, and festering woundsNo significant difference in survival rate between test and controlsAA-treated (10 ppm) embryos significantly reduced glomerular filtration rates compared with the control. Malformed kidney phenotypes, curved, cystic pronephric tubes, pronephric ducts, and cases of atrophic glomeruli were reported[39]Not compared
8PsoralenPsoralea corylifolia LPsoriasis, vitiligo, osteoporosis, osteosarcoma, bone fracture, and osteomalaciaThe values of LC50, LC10, and LC1 at 96 hpf were determined to be 18.24, 13.54, and 10.61 μM. The hatching rate in the 13.54 mM psoralen group (70%)Yolk retention, swim-bladder deficiency, pericardial oedema, and curved body shape were observed at 24 to 96 hpf in psoralen-treatment embryos.[40]Not compared
9Isofraxidin 7-O-(6’-O-p-coumaroyl)-β-glucopyranosideArtemisia capillaris ThunbergEnhanced pigmentation.Greater than 90% of the treated embryos survived, which did not differ significantly from the control group.The results revealed compound 1 (25 μM) treated embryos had no developmental defects and displayed normal cardiac function, indicating that this compound enhanced pigmentation without producing toxicity[41]Not compared
10EvodiamineBioactive alkaloidEvodia rutaecarpaAbdominal pain, headache, menstrual problems, vomiting, and diarrheaConcentrations ≥400 ng/mL significantly increased the lethality reached 100% at 1600 ng/mL evodiamine10% lethal concentration of 354 ng/mL and induced cardiac malfunction, as evidenced by changes in heart rate and circulation, and pericardial malformations[42]Primary cultured neonatal rat cardiomyocytes
11Tanshinone IIA (Tan-IIA)Diterpene quinoneSalvia miltiorrhiza BungeRecommended for cardiovascular disease exhibits various pharmacological activities, including anti-inflammatory, antioxidative, antifibrosis, modulation of collagen metabolism, and antitumourThe LC50 values in the dechorionated embryo group at 72 hpf and 96 hpf were 18.5 μM and 12.8 μM, respectively.
Normal embryos were less sensitive
Pericardial oedema at 6 μM for 96 hpf and spinal curvature higher concentrations were cardiotoxic[43]Not compared
12Gambogic acid (GA)Garcinia hanburyi Hook.f.,AnticancerThe LC50, LC10, MNLC and EC50 values were calculated as 1.76 μM, 0.8 μM, 0.5 μM and 0.723 μM, respectivelyGA at 0.5–1.0 μM caused specific fin developmental defect with the phenotype resembled those caused by thalidomide[44]Not compared
13Aconitine (AC), Mesaconitine (MAC,) Hypaconitine (HAC)
14-A-benzoylaconine (BAC), 14-a-Benzoylmesaconine (BMAC) Benzoylhypaconine (BHAC)
Diterpene alkaloids (Das)
Monoester diterpene alkaloids (MDA)
Aconitum, Delphinium, Consolida, and Spiraea speciesAnti-inflammation, antidepressant, antiarrhythmia, antiplatelet aggregation, and antimalarial propertiesNot investigatedDiterpenes including AC, MAC, and HAC exhibited serious organic and functional toxicities in zebrafish embryos compared with that of monoester diterpene alkaloid[45]Not compared