TABLE 1.
Risk substances, toxicity evaluation, and potential mechanisms of some representative CMM-induced cardiotoxicity in vivo and in vitro.
| Risk substances | Toxicity evaluation | Potential mechanisms | References | |||
|---|---|---|---|---|---|---|
| Category | Risk compounds | CMM | Models and dosage | Measurement indicators | ||
| Alkaloids | Aconitine | Aconitum carmichaelii Debeaux. | Primary culture of neonatal rat ventricular myocytes (NRVMs): 0–160 μmol/l for 7 days; AC-16 cells: 0–320 μmol/l for 24 h | Cell viability, mito-SOX (AC-16 cells), Notch1, NICD, HES1, c-Myc, CK2α, KDM5A, p300, RBP-J, HCN 4, I f current, action potential, and beating rate | Involvement of Notch1/NICD/KDM5A/HCN4 toxicity pathway | Zhou et al. (2020) |
| Aconitum sp. | Male Sprague–Dawley (SD) rats: 1.0 mg/kg/day by gavage for 7 days; H9c2 and rat primary cardiocyte cells: 0.5, 1, and 2 μmol/l for 24 h | ROS, mitochondria damage, TNF-α, FADD, Fas/Fas-L, cytochrome C, Bcl-2, caspase-3, caspase-8, RIP1, RIP3, MLKL, NLRP3, ASC, caspase-1, IL-1β, LC3-II (mitochondria), BNIP3, ULK1, LC3, and p62 | Mitigation of BNIP3-dependent mitophagy and activation of the TNF-α-NLRP3 inflammatory pathways | Peng et al. (2020) | ||
| Aconitum carmichaelii Debeaux. | Zebrafish embryo (cmlc2:eGFP): 1.87–30.0 μmol/l for 48 h; H9c2 cells: 0.75–6.0 mmol/l for 30 min | Survival rate, HR, the contraction of ventricles and atria, cell viability, intracellular Ca2+ concentrations, gene expression profile, cacna1c, RYR2, ATP2a2b, cTnC, Myh6, cTnT, p38, caspase-3, Bcl-2, and Bax | Ca2+ overload and cell apoptosis | Li et al. (2020) | ||
| Hypaconitine | Aconitum sp. | Human embryonic kidney (HEK)-293 cells: 1, 3, 10, and 30 nmol/l; beagle dogs: 50, 150, and 450 μg/kg/day for 6 h | QTc interval and KCNH2 currents | Inhibition of KCNH2 potassium channels | Xie et al. (2015) | |
| Lappaconitine | Aconitum sp. | HEK-293 cells:10–100 μmol/l for 25–30 min | hH1 channels | Irreversible blockade of hH1 channels by binding to the site 2 receptor | Wright, (2001) | |
| Berberine | Berberis sp. or Coptis sp. | Guinea pigs: 27.1 mg/kg/day by gavage once; HEK-293 cells: 1 and 10 μmol/l for 24 h | HSP90, mature-155 kDa hERG, immature-135 kDa hERG, ATF6, calnexin, calreticulin, the colocalization between hERG and calnexin/calreticulin, hERG current, APD, and QTc interval | Induction of hERG channel deficiency by trafficking inhibition | Zhang et al. (2014) | |
| Evodiamine | Evodia rutaecarpa (E. rutaecarpa) | NRVMs: 31.3–250 μg/mL for 24 h; Zebrafish: 200–1,600 ng/mL for 24 h | Cell viability, LDH release, MDA, HR, heart malformation, pericardial edema, circulation abnormalities, thrombosis and hemorrhage, and SV-BA distance | Involvement of oxidative stress | Yang et al. (2017) | |
| Strychnine, brucine, and their N-oxide | Strychnos nux-vomica L. (Loganiaceae) | Male SD rats: 0.3 mg/kg and 0.6 mg/kg intravenously once; HEK 293 cells: 20–500 μmol/l for 10 min | QT interval and hERG channels | Inhibition of hERG channels | Yuan et al. (2018) | |
| Matrine, oxymatrine, cytisine, and sophocarpine | Sophora tonkinensis Gapnep. (S. tonkinensis) | hiPSC-CMs: 2, 10, and 50 μmol/l for 24 h | Cell viability, LDH, CK-MB, cTnI, SOD, GSH, ROS, MDA, and intracellular calcium | Induction of oxidative stress and disruption of calcium homeostasis | Wang et al. (2019b) | |
| Arecoline, guvacoline, and arecaidine | Areca catechu L. | Male Wistar rats: 4,500 mg/kg/day with arecae semen aqueous extract by gavage for 30 days | Body weight, CK, arachidonic acid, PGE2, l-tryptophan, linoleic acid, α-linolenic acid, oleic acid, palmitic acid, palmitoleic acid, and stearic acid | Disturbance of phospholipids, amino acids, and arachidonic acid metabolism | Lin et al. (2020) | |
| Terpenoids | Triptolide | Tripterygium wilfordii Hook. F. | Male SD rats: 0.1 mg/kg by gavage for 14 days | Heart/body ratio, HR, myocardial fiber breakage, cardiomyocyte hypertrophy, cell gaps, nuclear dissolution, LDH, CK-MB, CAT, GSH, GSH-PX, plasma cTnI and GzmB, myocardial AhR, plasma AhR, CYP1 A1, and microRNAs | Changes in the expression of microRNAs and AhR | Wang et al. (2019c) |
| Tripterygium wilfordii Hook. F. | H9c2 cell and primary rat cardiomyocyte: 0–640 nmol/l or 160 nmol/l for 2–24 h.; p53−/− mice: 1.2 mg/kg intravenously once | Glucose (culture medium), ATP, LDH leakage, cell morphology, p65 (nuclei and cytoplasm), IKKβ, IκBα, N-p65/Histone3 p65, GLUT1, GLUT4, glucose uptake, TIGAR, Pgam2, and Pdk2 | p53 mediates cardiac injuries via dysregulation of glucose uptake by blocking the IKKβ-NF-κB pathway | Xi, Zhang et al. (2020) | ||
| Celastrol | Tripterygium wilfordii Hook. F. | Male Wistar rats: 0.5, 1, and 2 mg/kg by gavage for 7 days | Histopathological evaluation, MDA, SOD, valine, palmitic acid, sphingosine, lysophosphatidylcholine, 3-indolepropionic acid, 9-octadecenal, caspase-3, caspase-8, Bax, and Bcl-2 | Palmitic acid–induced oxidative stress-regulated TNF/caspase axis | Liu, Zhang et al. (2019) | |
| Rhodojaponin I, II, and III | Rhododendron molle G. Don (Ericaceae) | Male SD rats: 21.44 and 112.56 mg/kg with Rhododendri Mollis Flos extract by gavage once | HR, LVSP, LVDP, maximum rate of developed left ventricular pressure (dP/dtm), maximum rate of decreased left ventricular pressure (-dP/dtm), ST-segment, LDH, CK-MB, and AST | Dong et al. (2014) | ||
| Steroids | Oleandrin and other cardiac glycosides | Nerium oleander L. | Male guinea pigs: 150 and 300 mg/kg/day with hydroalcoholic extract of oleander by gavage once; ventricular myocytes: 0.3 and 10 mg/mL with hydroalcoholic extract of oleander | ECG, mitochondrial structure, electron density, cardiac fiber, cardiac excitability, global Ca2+ transients, and Na+/K+-pump current | Inhibition of Na+/K+- pump, mitochondrial damage, and disturbance of calcium homeostasis | Botelho, Santos-Miranda et al. (2017) |
| Periplocin | Periploca sepium Bge. | Neonatal rat cardiomyocytes: 0.2 and 0.4 mmol/l for 24 h | Tryptophan, carnitine, acetylcarnitine, citric acid, glutamic acid, pyroglutamic acid, leucine, pantothenic acid, indoleacrylic acid, proline, and lysophosphatidylcholine | Disruption of amino acid metabolism, energy metabolism, and sphingolipid metabolism | Li et al. (2016a) | |
| Bufo steroids | Bufo bufo gargarizans Cantor; Bufo melanostictus Schneider | Male SD rats: 100, 200, and 400 mg/kg by gavage for 48 h | HR, ST-segment, CK, CK-MB, ALT, AST, IL-6, IL-1β, TNF-α, MDA, SOD, CAT, GSH, GPX,TXNIP, NF-κB p65, IκBα, IKKα, IKKβ, ERK, JNK, and p38 | Promotion of inflammatory response through the TXNIP/TRX/NF-κB and MAPK/NF-κB pathways | Bi et al. (2016) | |
| Bufalin | Bufo bufo gargarizans Cantor; Bufo melanostictus Schneider | Neonatal cardiac myocytes and adult rat cardiomyocytes: 40 and 400 ng/mL Chan Su extract, 4 and 20 ng/mL bufalin | Calcium transients, intracellular calcium, and Na+-K+ ATPase | Blockage of Na+- K+-ATPases and disturbance of calcium homeostasis | Roger et al. (2002) | |
| Others | Arsenic trioxide | Arsenolite | HEK-293 cells and NRVMs: 3 μmol/l for 24 h | I Ca,L, APD, hERG channel, and Cav-1 | Involvement of Cav-1 expression and promotion of hERG degradation | Yan et al. (2017) |
| Arsenolite | Male BALB/c mice: 1 mg/kg/day via the tail vein for 2 weeks; ARVMs: 100 μmol/l for 20 min | Cardiomyocyte contractile function, intracellular Ca2+ transients, SERCA activity, SERCA2a, NCX, PLB, CaMKII, GRP78, PERK, eIf2α, IRE1, ATF6, CHOP, and caspase-12 | Disturbance of Ca2+ homeostasis and ER stress-associated apoptosis | Zhang et al. (2017) | ||
| Arsenolite | BALB/c mice: 1, 2, and 4 mg/kg/d via i.p. for 3, 7, and 14 days, H9c2 cell:0–10 µnol/l for 24 h | Mitochondrial structure, mPTP opening, ROS, ATP content, PGC-1α, DRP1, MFN1, MFN2, and OPA1 | Cardiac mitochondrial damage and impaired energy metabolism | Zhang et al. (2018a) | ||
| Aristolochic acid | Aristolochia sp.; Asarum L. | Zebrafish embryos: 1, 5, 10, and 20 μmol/l for 2–48 h | HR, cardiac phenotypes, COX-2, IL-1β, serum amyloid α, CCAAT/enhancer-binding protein B (C/EBPB), and C/EBPG | Induction of inflammatory response | Huang et al. (2007) | |
| Calcium oxalate needle crystal and lectin protein | Pinellia ternata (Thunb.) Breit. | SD rats: 3 g/kg/day with Pinelliae Rhizoma and its processed products by gavage for 14 days | Body weight, CK, CK-MB, LDH, histopathological evaluation, proline, leucine, tyrosine, saccharopine, 5-HT, dihydrouracil, KMTB, kynurenine, dhS1P, p-aminobenzoic acid, TGF-β1, mTOR, and MDA | Induction of inflammatory response through inhibiting mTOR signaling and activating the TGF-β pathway | Su et al. (2016) | |
| Aag-FG50 (scorpion toxin) | Androctonus australis hector | Mongrel dogs: 0.05 mg/kg of the purified venom toxic fraction by intravenous injection once | HR, mean arterial pressure, pulmonary artery occluded pressure, cardiac output, stroke volume, systemic vascular resistances, serum lactate, epinephrine, norepinephrine, neuropeptide Y, endothelin-1, and atrial natriuretic peptide | Disturbance of hemodynamic by excessive catecholamines release | Nouira et al. (2005) | |