Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation
Abstract
:1. Introduction
Medicinal Product | Class | Mechanism of Action | Launch Date | Year Withdrawn | Side Effects on Cardiac Function | Mitohondrial Toxicity |
---|---|---|---|---|---|---|
Amfepramone | Psychostimulant | Norepinephrine-releasing agent | 1957 | 1975 | - | Unknown |
Benfluorex | Psychostimulant, anorectic, and hypolipidemic | Blocking of 5-HT2B | 1976 | 2009 | Valvular heart disease | Decrease in CPT I expression [46] |
Emetine (ipecac syrup) | Emetic | Stimulation of the CTZ, local irritation | 1912 | 1982 | - | Unknown |
Mephenesin | Muscle relaxant | Spinal reflex inhibition | 1948 | 1976 | - | Unknown |
Rofecoxib | NSAID | COX-2 inhibitor | 1999 | 2004 | MI, cardiovascular thrombotic events, sudden death | Unknown |
Adenosine phosphate | Antiarrhythmic | Direct nodal inhibition | 1930 | 1973 | - | Unknown |
Alphacetylmethadol | Analgesic | OP1 receptor agonist | 1993 | 2003 | - | Unknown |
Bepridil (Bepridil Hydrochlonde) | Antiarrhythmic, antianginal | Calcium channel blockers | 1981 | 2004 | Prolonged QT, TdP | Unknown |
Budipine | Antiparkinsonian | Muscarinic and NMDA receptor antagonist | 1979 | 2000 | - | Unknown |
Cliobutinol | Antitussive | Unclear | 1961 | 2007 | - | Unknown |
Dofetilide | Antiarrhythmic | Inhibition of KCNH2, KCNK2, KCNJ12 | 1999 | 2004 | QT prolongation, TdP | Unknown |
Dolansetron | Propulsive | 5-HT3 receptor antagonist | 1997 | 2011 | - | Unknown |
Encainide | Antiarrhythmic | Na channel blocker | 1985 | 1991 | QT prolongation, TdP | Unknown |
Grepafloxacin (Grepafloxacin Hydrochloride) | Antimicrobial | Inhibition of DNA gyrase | 1997 | 1999 | QT prolongation | Unknown |
Indoramin | Vasodilator | Alpha-1 adrenoceptor antagonist | 1981 | 2011 | - | Unknown |
Isoprenaline | Cardiac stimulant | Non-selective beta-adrenergic agonist | 1949 | 1992 | - | mPTP opening [47] |
Inhibition of OXPHOS [48] | ||||||
Levacetylmethadol | Antidote | Mu-opioid receptor agonist, nicotinic acetylcholine receptor antagonist | 1995 | 2001 | - | Unknown |
Nifedipine (10 mg) | Antihypertensive, antiemetic | Calcium channel blockers | 1975 | 1996 | Hypertension, angina, MI, CHF | Inhibition of ATP synthase [48] |
Orciprenaline (metaprotenerol) | Bronchodilator | β2 adrenoceptor agonist | 1961 | 2009 | Tachycardia, palpitations | Unknown |
Pergolide Mesylate | Anti-parkinsonian | Dopamine receptor agonist | 2002 | 2007 | Valvular heart disease | Unknown |
Rosiglitazone | Hypoglycemic | Gluconeogenesis decrease | 1999 | 2011 | CHF, MI | Inhibition of ETC [48] |
Increase in mitochondrial oxidative stress, impairment of mitochondrial bioenergetics [13] | ||||||
Inhibition of complex I; uncoupling of OXPHOS [13] | ||||||
Sibutramine (Sibutramine Hydrochlonde Hydrate) | Psychostimulant | Serotonin-norepinephrine reuptake inhibitor | 2001 | 2002 | Myocardial infarction | Increase in ROS formation [49] |
Technetium (99mTc) fanolesomab | Radiography | Radioisotope | 2004 | 2005 | Cardiopulmonary arrest | Unknown |
Tegaserod (Tegaserod Maleate) | Antispasmodic | 5-HT4 receptor agonist | 2002 | 2007 | HF, ischemia | Unknown |
Terodiline | Antispasmodic | Calcium channel blockade, blocks cholinergic receptor | 1965 | 1991 | Ventricular tachycardia, cardiac death | Unknown |
Sertindole | Antipsychotic | 5HT and D2 receptor antagonist/blocking of DRD2,HTR2A, HTR2C, HTR6 | 1996 | 1998 | QT prolongation, TdP, sudden cardiac death | Unknown |
Cloforex | Psychostimulant | Similar to amphetamine | 1965 | 1967 | - | Unknown |
Astemizole | Antihistamine | H1-receptor antagonist, inhibition of KCNH2 | 1977 | 1987 | long QT syndrome, TdP | Unknown |
Cisapride monohydrate | Prokinetic agent | 5-HT4 receptor agonist; inhibition of KCNH2 | 1993 | 2000 | Ventricular arrhythmia, QT prolongation, TdP, cardiac arrest | Unknown |
Tranylcypromine | Antidepressant | MAOI | 1961 | 1964 | - | Unknown |
Bromocriptine mesylate | Anti-lactation | D2 and D3 agonist | 1976 | 1989 | - | Swollen mitochondria [50] |
Domperidone (injectable) | Propulsive | Dopamine receptor antagonist | 1979 | 1985 | - | Unknown |
Mepazine | Antiepileptic | Unclear | 1955 | 1970 | - | Unknown |
Clozapine | Antipsychotic | Blocking of DRD2, HTR2A, DRD1, DRD3, DRD4, HTR1A, HTR1B, HTR1D, HTR1E, HTR2C, HTR3A, HTR6, HTR7, HRH1, HRH4, ADRA1A, ADRA1B, ADRA2A, ADRA2B, ADRA2C, CHRM1, CHRM2, CHRM3, CHRM4, CHRM5 | 1972 | 1975 | Cardiomyopathy, MI, myocarditis, arrhythmia, Prolonged QT, TdP, cardiomyopathy | Inhibition of the ETC [51] |
Increase in ROS formation, GSH depletion, mitochondrial dysfunction, and swelling [52] | ||||||
Vincamine | Nootropic | Unclear | 1955 | 1980 | - | Unknown |
Lysine amidotriazoate | Radiography | - | 1975 | 1995 | - | Unknown |
Terfenadine | Antihistamine | H1-receptor antagonist | 1985 | 1997 | QT prolongation, TdP | Increase in mtROS formation [53] |
MMP collapse [54] | ||||||
Naftidrofuryl oxalate (IV) | Vasodilator | 5HT2 receptor antagonist | 1974 | 1992 | - | Unknown |
Cobalt | Hematinic | As cobalamin | 1951 | 1967 | - | Interruption of TCA and interference with the MRC enzymes [54] |
MMP collapse [55] | ||||||
Chloroform (trichloromethane) | Anesthetic | Depression of the respiratory centres | 1847 | 1976 | - | MMP collapse [56] |
Megamitochondria [57] | ||||||
Dithiazanine iodide | Antihelminth | Interruption of glucose uptake in cells | 1959 | 1964 | Prolonged QT, TdP | Unknown |
Epinephrine (topical) | Anesthetic | Vasoconstriction | 1899 | 2004 | - | Unknown |
Methylhexanamine (DMAA) | Nasal decongestant | Norepinephrine and dopamine transporter blockade | 1948 | 1983 | - | Unknown |
Dexfenfluramine | Psychostimulant | Serotonin receptor agonist | 1995 | 1997 | Valvular heart disease, cardiac fibrosis | Unknown |
Fenfluramine | Psychostimulant | Serotonin receptor antagonist | 1973 | 1997 | valvular heart disease | Mitochondrial fragmentation [58] |
Parecoxib | Analgesic | COX-2 inhibitor | 2002 | 2005 | - | - |
Prenylamine | Antianginal | Calcium channel blocker | 1960 | 1989 | QT prolongation, sudden cardiac death, ventricular tachycardia, TdP | Inhibition of FAO [59] |
Probucol | Antioxidant | Inductor of LDL catabolism | 1980 | 1989 | QT prolongation, arrhythmias | Unknown |
Droperidol | Antipsychotic | Dopamine 2 receptor antagonist | 1970 | 2001 | - | Unknown |
Valdecoxib | NSAID | COX-2 inhibitor | 2001 | 2005 | Cardiomyopathy, CHF, hypertension, angina, arrhythmia | Inhibition of OXPHOS, mPTP opening [16] |
Celecoxib (Onsenal) | NSAID | COX-2 inhibitor | 2003 | 2011 | - | Decrease in mitochondrial complex IV activity and induces oxidative stress [14] |
Increase in ROS formation, MMP collapse, mitochondrial swelling, ATP depletion [60] | ||||||
Suppression of mitochondrial function [61] | ||||||
Bismuth salts | Antidyspepsia | Unclear. Forms insoluble complexes | 1875 | 1978 | - | Unknown |
Levarterenol | Vasopressor | L-norepinephrine analogue | 1904 | 1973 | - | Unknown |
Pipradrol | Psychostimulant | Norepinephrine-dopamine reuptake inhibitor | 1953 | 1982 | - | Unknown |
Pseudoephedrine | Sympathomimetic | Direct action on adrenergic receptors | 1959 | 2008 | - | Unknown |
Gallopamil | Antiarrhythmic | Calcium channel blockers | 1983 | 2001 | - | Decrease in mitochondrial biogenesis and mass [62] |
Chlorphentermine | Psychostimulant | TAAR1 agonist, blocking of 5-HTs | 1962 | 1969 | Pulmonary heart disease | Inhibition of OXPHOS, uncoupling of OXPHOS [63] |
Thioridazine | Antipsychotic | 5HT2 receptor antagonist | 1959 | 2000 | QT prolongation, TdP, sudden cardiac death | mPTP opening [64] |
MMP collapse [65] | ||||||
Buflomedil | Vasodilator | A-adrenergic blockade | 1970 | 2006 | QT prolongation, cardiac arrest | Unknown |
Ponatinib Hydrochloride | Antineoplastic | Multi-target kinase inhibitor | 2012 | 2013 | - | Impairment of respiratory chain, increase in ROS formation, MMP collapse, mitochondrial fission [66] |
Levomethadyl acetate | Analgesic (central nervous system agents) | Activation of OPRM1 | 1993 | 2002 | QT prolongation, TdP | Unknown |
Mesoridazine Besylate | Antipsychotic | 1970 | - | - | Unknown | |
Clobutinol Hydrochloride | Antitussive | Inhibition of GABA receptors | 1961 | 2007 | QT prolongation | Unknown |
Phentermine | Central nervous system agents | Inhibition of SLC6A2, SLC6A3, SLC6A4; blockingof MAOA, MAOB | 1959 | 1997 | Valvular heart disease | Unknown |
Mibefradil | Antihypertensive | Calcium channel blockers | 1997 | 1998 | QT prolongation | Unknown |
Sparfloxacin | Antibiotics | Inhibits DNA gyrase | 1997 | 2001 | QT prolongation | MMP collapse [67] |
Etoricoxib | Anti-inflammatory agents | Inhibition of COX-2 | 2002 | 2007 | thrombotic events | Inhibition of OXPHOS [16] |
Propoxyphene | Central nervous system agents | Activation of OP1, OP2, OP3 | 1957 | 2010 | QT prolongation, TdP | Unknown |
Lidoflazine | Cardiovascular agents | Blocking of calcium channels | 1973 | 1989 | QT prolongation | Unknown |
2. Main Properties of Mitochondria and Drug-Induced Mitochondrial Toxicity in Cardiomyocytes
2.1. Morphology, Classification, and Structural Features of Mitochondria
2.2. Substrate Catabolism and OXPHOS
2.3. Mitochondrial ROS (mtROS)
2.4. Replication, Translation, and Transcription of mtDNA
2.5. Mitochondrial Membrane Potential (MMP) and mPTP
Modules | Alterations | Pharmacology | Drugs | Clinical Manifestations | Cmax | Models | Dose | Time | References |
---|---|---|---|---|---|---|---|---|---|
Carrier | Downregulation of CPT I expression | Alkylating agent | Cyclophosphamide | HMC, CMP | 143 μM | Male Wistar rats (IP) | 200 mg/kg | 10 d | [189] |
Carrier | Downregulation of CPT I expression | Anesthesia | Propofol | HF, arrhythmia | 30.13 μM | HiPSC-CMs | 10 µg/mL | 48 h | [163] |
Carrier | Downregulation of CPT I expression | TKIs | Sunitinib | Decreased LVEF, QT prolongation, TdP, hypertension, HF, CMP | 0.25 μM | Rats (oral) | 25 mg/kg/d | 28 d | [173] |
Carrier | Inhibition of CPT1 activity | Anti-arrhythmic drug | Dronedarone | AF, HF | 0.15–0.26 μM | Isolated rat heart mitochondria | IC50 = 40 µM | 20 min | [139] |
Carrier | loss of carnitine | Co-catalyst | Pivalic acid | CMP | [232] | ||||
Carrier | Inhibition of ANT | NSAIDs | Diclofenac | Hypertension, arrhythmias | 7.9 µM | Submitochondrial particles | 314 nM/mg protein diminished 76% | [142] | |
Nimesulide | Submitochondrial particles | 259 nM/mg protein diminished 60% | [142] | ||||||
Carrier | Inhibition of ANT | NRTIs | Zidovudine | CMP | 4 μM | [233] | |||
mtDNA | Inhibition of mitochondrial DNA polymerase | NRTIs | Zidovudine | CMP | 4 μM | Cardiac DNA pol-γ | 1 µM | [234] | |
mtDNA | Inhibition of topoisomerase II | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | - | - | - | [235] |
Daunorubicin | CMP, MI, CHF, VA, pericarditis, myocarditis | 89 μM | - | - | - | [207] | |||
Idarubicin | CMP, MI, CHF, VA, decreased LVEF | 23.22 μM | - | - | - | [207] | |||
mtDNA | Inhibition of topoisomerase II | Chemotherapeutic agents | Mitoxantrone | CHF, CMP, decreased LVEF, arrhythmia | 3.3 μM | - | - | - | [215] |
mtDNA | mtDNA content decreasing | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male Wistar rats (IV) | 1 mg/kg/w | 7 w (started at 11 w, observed at 48 w) | [96] |
mtDNA | mtDNA content decreasing | TKIs | Regorafenib | MI; hypertension | 8.08 μM | H9c2 | 5 μM | 72 h | [90] |
2.6. Mitochondrial Carriers
2.7. Mitochondrial Quality Control (MQC)
2.8. Other Mitotoxicants and Their Targets
3. Limitations of Current Preclinical Models for Assessing Cardiotoxicity
3.1. Limitations in the Current Workflow of Cardiac Safety Testing
3.2. In Vitro Models for Cardiac Toxicity Assessment
3.2.1. H9c2 Cardiomyoblasts
3.2.2. Stem-Cell-Derived Cardiomyocytes
3.2.3. hPCMs
3.2.4. 3D Cardiomyocyte Models
4. Proposed Preclinical Model of Cardiomyocytes for Assessment of Drug-Induced Mitochondria Toxicity
4.1. In Vitro Cell Culture for Cardiotoxicity Assays
4.2. Mitochondrial Target as Readouts in Cardiotoxicity Assays
4.2.1. Mitochondrial Morphology, Structure
4.2.2. Oxygen Consumption Rate (OCR)
4.2.3. ATP
4.2.4. Redox Homeostasis
4.2.5. MMP
4.3. High-Throughput Assessment of Mitochondrial Toxicity
4.4. Proposed Integrated Assays for Drug-Induced Mitochondria Toxicity of Cardiomyocytes
5. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Modules | Alterations | Pharmacology | Drugs | Clinical Manifestations | Cmax | Models | Dose | Time | References |
---|---|---|---|---|---|---|---|---|---|
Morphology | Mitochondrial swelling | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male Wistar rats (IP) | 2&2.5 mg/kg/2 d | 2 w | [94] |
Male Wistar rats (IP) | 2.5 mg/kg/2 d | 2 w | [95] | ||||||
Male Wistar rats (IV) | 1 mg/kg/w | 7 w (started at 11 w, observed at 48 w) | [96] | ||||||
Idarubicin | CMP, MI, CHF, VA, decreased LVEF | 23.22 μM | Male SD rats (IV) | 5 mg/kg/w | 6 w | [110] | |||
Morphology | Mitochondrial swelling | Alkylating agent | Cyclophosphamide | HMC, CMP | 143 μM | Male Wistar rats (IP) | 200 mg/kg | 10 d | [111] |
Morphology | Mitochondrial swelling | Chemotherapeutic agents | Cisplatin | Decreased LVEF, arrhythmias, ECA, myocarditis, CMP | 27.54 μM | C57BL mice (IV) | 10 mg/kg/d | 1 w | [112] |
Morphology | Mitochondrial swelling | Monoclonal antibody | Trastuzumab | CMP, LVD, CHF | 2.59 mM | Female white New Zealand rabbits (SC) | 8 mg/kg, a single dose; 8 mg/kg first w, 6 mg/kg for three additional w | 4 w | [113] |
Morphology | Mitochondrial swelling | TKIs | Sunitinib | Decreased LVEF, QT prolongation, TdP, hypertension, HF, CMP | 0.25 μM | Patient | [114] | ||
Male SD rats (oral) | 10 mg/kg/d | 3 w | [89] | ||||||
Morphology | Mitochondrial swelling | NSAIDs | Diclofenac | Hypertension, arrhythmias | 7.9 µM | Isolated rat heart mitochondria | 10 µg/mL | 1 h | [115] |
Isolated rat heart mitochondria | 50 μM | 1 h | [60] | ||||||
Naproxen | - | 100 µM | Isolated rat heart mitochondria | 25 μM | 1 h | [60] | |||
Celecoxib | Thrombosis, MI, stroke | 3–5 µM | Isolated rat heart mitochondria | 100 μM | 1 h | [60] | |||
Morphology | Mitochondrial swelling | NRTIs | Zidovudine | CMP | 4 μM | Rats (oral) | 125 mg/kg/d | 4 w | [116] |
Morphology | Mitochondrial swelling | Cardiac glycosides | Nerium oleander L. | PVB, AVB, VT | - | Guinea pigs (oral) | 150&300 mg/kg | 3 h | [117] |
Morphology | Mitochondrial swelling | β-adrenoceptor agonists | Isoproterenol | HF | 0.01 μM | Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [118] |
Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [83] | ||||||
Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [82] | ||||||
Propranolol | Cardiotoxicity | 0.22 μM | Isolated rat heart mitochondria | 5 µg/mL | 5 min | [119] | |||
Atenolol | Cardiotoxicity | 4.99 μM | Isolated rat heart mitochondria | 10 µg/mL | 5 min | [119] | |||
Morphology | Mitochondrial swelling | Macrolide antibiotics | Azithromycin | Arrhythmia | 0.32–0.87 μM | Isolated rat heart mitochondria | 25 μM | 1 h | [120] |
Clarithromycin | TdP | 2.67–13.37 μM | Isolated rat heart mitochondria | 50 μM | 1 h | [120] | |||
Erythromycin | TdP | 11 μM | Isolated rat heart mitochondria | 25 μM | 1 h | [120] | |||
Morphology | Mitochondrial swelling | Aconitum species | Aconitum sp. | VA | 19.27 μg/ml | H9c2 | 1 μM | [121] | |
Morphology | Mitochondrial swelling | Diabetes medication | Pioglitazone | HF | 2.6 μM | Isolated rat heart mitochondria | 12.5 µg/mL (30 min), 25 µg/mL (5 min) | [122] | |
Morphology | Morphological damage | NRTIs | Zidovudine | CMP | 4 μM | H9c2 | 50 μM | 39 passages | [123] |
Didanosine | CMP | 12 μM | H9c2 | 50 μM | 10 passages | [123] | |||
Structure | Cristae disappearance | Chemotherapeutic agents | As2O3 | QT prolongation TdP, CMP, tachycardia | 12.1 μM | Male BALB/c mice | 2 mg/kg | 14 d | [84] |
Structure | Cristae disappearance | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male Wistar rats (IP) | 2&2.5 mg/kg/2 d | 2 w | [94] |
Male Wistar rats (IP) | 2.5 mg/kg/2 d | 2 w | [95] | ||||||
Kunming mice (IP) | 2 mg/kg | 10 d | [102] | ||||||
Male Wistar rats (IV) | 1 mg/kg/w | 7 w (started at 11 w, observed at 48 w) | [96] | ||||||
Structure | Cristae disappearance | Alkylating agent | Cyclophosphamide | HMC, CMP | 143 μM | Male Wistar rats (IP) | 200 mg/kg | 10 d | [111] |
Male Wistar rats (IP) | 200 mg/kg | 10 d | [124] | ||||||
Patient | [125] | ||||||||
Structure | Cristae disappearance | TKIs | Sorafenib | Bleeding, hypertension,QT prolongation, CHF, CI, MI | 16.6 μM | Male SD rats (oral) | 10 mg/kg/d | 3 w | [89] |
Structure | Cristae disappearance | NRTIs | Zidovudine | CMP | 4 μM | Rats (oral) | 125 mg/kg/d | 4 w | [116] |
Pregnant CD-1 mice + pups,oral | 75 mg/kg, BID | 2 w prior to pregnancy to pups postnatal 28 d | [126] | ||||||
Structure | Cristae disappearance | β-adrenoceptor agonists | Isoproterenol | HF | 0.01 μM | Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [118] |
Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [83] | ||||||
Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [82] | ||||||
Structure | Cristae disorganization | Monoclonal antibody | Trastuzumab | CMP, LVD, CHF | 2.59 mM | Female white New Zealand rabbits (SC) | 8 mg/kg, a single dose; 8 mg/kg first W, 6 mg/kg for three additional w | 4 w | [113] |
Structure | OMM or/and IMM disruption | NRTIs | Zidovudine | CMP | 4 μM | Rats (oral) | 125 mg/kg/d | 4 w | [116] |
Monoclonal antibody | Trastuzumab | CMP, LVD, CHF | 2.59 mM | Female white New Zealand rabbits (SC) | 8 mg/kg for first w, 6 mg/kg for three additional w | 4 w | [113] | ||
Structure | Matrix clearout | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male Wistar rats, intraperitoneal(IP) | 2.5 mg/kg/2 d | 2 w | [95] |
Structure | Matrix clearout | TKIs | Sunitinib | Decreased LVEF, QT prolongation, TdP, hypertension, HF, CMP | Male SD rats (oral) | 10 mg/kg/d | 3 w | [89] | |
Regorafenib | MI; hypertension | H9c2 | 10 μM | 72 h | [90] | ||||
Structure | β-adrenoceptor agonists | Isoproterenol | HF | 0.01 μM | Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [118] | |
Matrix clearout | Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [83] | |||||
Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [82] | ||||||
Structure | Matrix clearout | Chemotherapeutic agents | Cisplatin | Decreased LVEF, arrhythmias, ECA, myocarditis, CMP | 27.54 μM | C57BL mice (IV) | 10 mg/kg/d | 1 w | [112] |
As2O3 | QT prolongation TdP, CMP, tachycardia | 12.1 μM | Male BALB/c mice | 2 mg/kg | 14 d | [84] | |||
MQC | Excessive mitophagy | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP QT prolongation TdP, CMP, tachycardia | 15.3 μM | AC16 cells | 15.625 nM | 24 h | [127] |
Adult rat cardiac myocytes | 1 μM | 4 h | [128] | ||||||
MQC | Excessive mitophagy | Chemotherapeutic agents | As2O3 | 12.1 μM | HL-1 | 6 μM | 6 h | [129] | |
MQC | Inhibition of mitophagy | Aconitum species | Aconitum sp. | VA | 19.27 μg/ml | H9c2 | 2 μM | 24 h | [121] |
MQC | Inhibition of mitochondrial biogenesis | Monoclonal antibody | Trastuzumab | CMP, LVD, CHF | 2.59 mM | - | - | - | |
MQC | Mitochondrial dynamics | TKIs | Sunitinib | Decreased LVEF, QT prolongation, TdP, hypertension, HF, CMP | 0.25 μM | - | - | - | [130] |
Regorafenib | MI; hypertension | 8.08 μM | H9c2 | 20 μM | 48 h | [90] | |||
MQC | Mitochondrial dynamics | NRTIs | Zidovudine | CMP | 4 μM | Pregnant CD-1 mice + pups, oral | 75 mg/kg, BID | 2 w prior to pregnancy to pups postnatal 28 D | [126] |
TMPK-overexpressing H9c2 cells | 100 µM | 24 h | [131] | ||||||
MQC | Mitochondrial dynamics | Nucleoside analogues | Remdesivir | Bradycardia, QT prologation, CA | 9 μM | hiPSC-CMs | 2.5 μM | 3 d | [86] |
MQC | Mitochondrial dynamics | Addictive drugs | Ethanol | H9c2 | 5 μM | 0.5 h | [132] |
Modules | Alterations | Pharmacology | Drugs | Clinical Manifestations | Cmax | Models | Dose | Time | References |
---|---|---|---|---|---|---|---|---|---|
OXPHOS | Inhibition of complex I | Cholesterol medications | Simvastatin | Cardiac atrophy | 0.02 μM | H9c2 | 10 μM | 24 h | [151] |
OXPHOS | Inhibition of complex I | β-adrenoceptor agonists | Isoproterenol | HF | 0.01 μM | Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [83] |
OXPHOS | Inhibition of complex I | Alkylating agent | Cyclophosphamide | HMC, CMP | 143 μM | Male Wistar rats (IP) | 200 mg/kg | 10 d | [111] |
Male Wistar rats (IP) | 200 mg/kg | 10 d | [124] | ||||||
OXPHOS | Inhibition of complex I | NRTIs | Zidovudine | CMP | 4 μM | Isolated mitochondria from H9c2 | 50 μM | 3 passages | [152] |
Didanosine | CMP | 12 μM | Isolated mitochondria from H9c2 | 50 μM | 3 passages | [152] | |||
OXPHOS | Inhibition of complex I | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male Wistar rats (IP) | 2.5 mg/kg/2 d | 2 w | [95] |
OXPHOS | Inhibition of complex I | Chemotherapeutic agents | As2O3 | QT prolongation TdP, CMP, tachycardia | 12.1 μM | Isolated mitochondria from H9c2 | 5 μM | 24 h | [141] |
OXPHOS | Inhibition of complex I | Anesthesia | Propofol | HF, arrhythmia | 30.13 μM | Cardiac muscle fibers of Wistar male rats | 0.025 mM | [153] | |
Halothane (fluothane) | - | 10 μM | Pig heart submitochondrial particles | Dose response curve | [154] | ||||
Inhibition of complex I | TKIs | Mubritinib | - | - | H9c2 | 0.5 μM | [140] | ||
OXPHOS | Inhibition of complex I | NSAIDs | Nabumetone | - | 2.45 μM | Submitochondrial particles | 55 nmol/mg protein inhibit 50% | [142] | |
Meclofenamate sodium | - | 3.55 μM | Mitochontria | 100 µM (70% inhibition) | [138] | ||||
Naproxen | - | 100 µM | Mitochontria | 200 µM (50% inhibition) | [138] | ||||
OXPHOS | Inhibition of complex I | Addictive drugs | Cocaine | Arrhythmias, angina, MI, HF | 0.76–0.94 µM | Isolated rat heart mitochondria | 1 μM | [155] | |
OXPHOS | Inhibition of complex I | Anti-arrhythmic drug | Amiodarone | LQT, TdP, Hypotension, AV block, Arrhythmia, heart block, SBC, CHF, VF | 4.65 μM | Isolated rat heart mitochondria | IC50 = 5.24 µM | [139] | |
Dronedarone | AF, HF | 0.15–0.26 μM | Isolated rat heart mitochondria | IC50 = 3.07 µM | [139] | ||||
OXPHOS | Inhibition of complex I | Immunosuppressant drug | Cyclosporine A | Cardiotoxicity | 0.5–5 µM | Enzymes and coenzymes | 100 µM | [156] | |
OXPHOS | Inhibition of complex II | NSAIDs | Diclofenac | Hypertension, arrhythmias | 7.9 µM | Isolated rat heart mitochondria | 10 µg/mL | 1 h | [115] |
Naproxen | - | 100 µM | Isolated rat heart mitochondria | 50 μM | 1 h | [60] | |||
OXPHOS | Inhibition of complex II | Alkylating agent | Cyclophosphamide | HMC, CMP Cardiotoxicity | 143 μM 0.22 μM | Male Wistar rats (IP) | 200 mg/kg | 10 d | [124] |
Male Wistar rats (IP) | 200 mg/kg | 10 d | [111] | ||||||
OXPHOS | Inhibition of complex II | β receptor blocker drugs | Propranolol | Isolated rat heart mitochondria | 10 µg/mL | 30 min | [119] | ||
Atenolol | Cardiotoxicity | 4.99 μM | Isolated rat heart mitochondria | 10 µg/mL | 30 min | [119] | |||
OXPHOS | Inhibition of complex II | Macrolide antibiotics | Azithromycin | Arrhythmia | 0.32–0.87 μM | Isolated rat heart mitochondria | 25 μM | 20 min | [120] |
Clarithromycin | TdP | 2.67–13.37 μM | Isolated rat heart mitochondria | 50 μM | 20 min | [120] | |||
Erythromycin | TdP | 11 μM | Isolated rat heart mitochondria | 25 μM | 20 min | [120] | |||
OXPHOS | Inhibition of complex III | Chemotherapeutic agents | As2O3 | QT prolongation TdP, CMP, tachycardia | 12.1 μM | Isolated mitochondria from H9c2 | 5 μM | 24 h | [141] |
OXPHOS | Inhibition of complex III | TKIs | Sorafenib | Bleeding, hypertension, QT prolongation, CHF, CI, MI | 16.6 μM | NRVMs | 4.5 µM | 20 min | [32] |
OXPHOS | Inhibition of complex III | Alkylating agent | Cyclophosphamide | HMC, CMP | 143 μM | Male Wistar rats (IP) | 200 mg/kg | 10 d | [111] |
7.9 µM | Male Wistar rats (IP) | 200 mg/kg | 10 d | [124] | |||||
OXPHOS | Inhibition of complex III | NSAIDs | Diclofenac | Hypertension, arrhythmias | Mitochondria isolated from mouse hearts | 5 µM | [157] | ||
Meclofenamate sodium | - | 3.55 μM | Mitochontria | 10 µM | [138] | ||||
Inhibition of complex III | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | - | 15 mg/kg | - | [158] | |
OXPHOS | Inhibition of complex IV | Alkylating agent | Cyclophosphamide | HMC, CMP HF | 143 μM 0.01 μM | Male Wistar rats (IP) | 200 mg/kg | 10 d | [111] |
Male Wistar rats (IP) | 200 mg/kg | 10 d | [124] | ||||||
OXPHOS | Inhibition of complex IV | β-adrenoceptor agonists | Isoproterenol | Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [83] | ||
OXPHOS | Inhibition of complex IV | Cholesterol medications | Simvastatin | Cardiac atrophy | 0.02 μM | H9c2 | 10 μM | 24 h | [151] |
OXPHOS | Inhibition of complex IV | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP, QT prolongation TdP, CMP, tachycardia | 15.3 μM 12.1 μM | Male Wistar rats (IP) | 2.5 mg/kg/2 d | 2 w | [95] |
Male Wistar rats (IV) | 1 mg/kg/w | 7 w(started at 11 w, observed at 48 w) | [96] | ||||||
OXPHOS | Inhibition of complex IV | Chemotherapeutic agents | As2O3 | Isolated mitochondria from H9c2 | 5 μM | 24 h | [141] | ||
OXPHOS | Inhibition of complex IV | NSAIDs | Celecoxib | Thrombosis, MI, stroke | 3–5 µM | Isolated rat heart mitochondria | 16 µg/mL | [14] | |
OXPHOS | Inhibition of complex IV | Proteasome inhibitor | Bortezomib | QT prolongation, hypotension | 0.3 μM | Male Wistar rats | 0.2 mg/kg | 3 w | [159] |
OXPHOS | Inhibition of complex IV | Immunosuppressant drug | Cyclosporine A | Cardiotoxicity | 0.5–5 µM | Enzymes and coenzymes | 100 µM | [156] | |
OXPHOS | Inhibition of complex V | Chemotherapeutic agents | Mitoxantrone | CHF, CMP, decreased LVEF, arrhythmia | 3.3 μM | Isolated rat heart mitochondria | 2.5 mg/kg on d 0, 10, and 20 | 22 d | [160] |
OXPHOS | Inhibition of complex V | Anticonvulsants | Phenytoin | Bradycardia, hypotension | 87.21 μM | guinea pig heart preparations | 1.0 nM | [161] | |
OXPHOS | Downregulation of complex I expression | TKIs | Regorafenib | MI; hypertension | 8.08 μM | H9c2 | 20 μM | 72 h | [90] |
OXPHOS | Downregulation of complex I expression | Nucleoside analogues | Remdesivir | Bradycardia, QT prologation, CA | 9 μM | HiPSC-CMs | 2.5 μM | 3 d | [86] |
OXPHOS | Downregulation of complex I expression | Addictive drugs | Ethanol | Male C57BL/6J mice | 10% (v/v) | 12 w | [162] | ||
OXPHOS | Downregulation of complex I expression | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male CD-1 mice (IP) | 9 mg/kg | 1 w | [100] |
Mitoxantrone | CHF, CMP, decreased LVEF, arrhythmia | 3.3 μM | Male CD-1 mice (IP) | 6 mg/kg | 1 w | [100] | |||
OXPHOS | Downregulation of complexe II expression | Anesthesia | Propofol | HF, arrhythmia | 30.13 μM | HiPSC-CMs | 10 µg/mL | 48 h | [163] |
Addictive drugs | Ethanol | Male C57BL/6J mice | 10% (v/v) | 12 w | [162] | ||||
OXPHOS | Downregulation of complex III expression | Addictive drugs | Ethanol | Male C57BL/6J mice | 10% (v/v) | 12 w | [162] | ||
Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male CD-1 mice (IP) | 9 mg/kg | 1 w | [100] | ||
OXPHOS | Downregulation of complex IV expression | Mitoxantrone | CHF, CMP, decreased LVEF, arrhythmia | 3.3 μM | Male CD-1 mice (IP) | 6 mg/kg | 1 w | [100] | |
Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male Wistar rats (IV) | 1 mg/kg/w | 7 w(started at 11 w, observed at 48 w) | [96] | ||
Addictive drugs | Ethanol | Male C57BL/6J mice | 10% (v/v) | 12 w | [162] | ||||
OXPHOS | Downregulation of complex V expression | Nucleoside analogues | Remdesivir | Bradycardia, QT prologation, CA | 9 μM | HiPSC-CMs | 2.5 μM | 3 d | [86] |
OXPHOS | Downregulation of complex V expression | TKIs | Regorafenib | MI; hypertension | 8.08 μM | H9c2 | 20 μM | 72 h | [90] |
OXPHOS | Downregulation of complex V expression | Proteasome inhibitor | Bortezomib | QT prolongation, hypotension | 0.3 μM | Male Wistar rats | 0.2 mg/kg | 1 w | [159] |
OXPHOS | Downregulation of complex V expression | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male CD-1 mice (IP) | 9 mg/kg | 1 w | [100] |
Mitoxantrone | CHF, CMP, decreased LVEF, arrhythmia | 3.3 μM | Male CD-1 mice (IP) | 6 mg/kg | 1 w | [100] | |||
OXPHOS | Downregulation of complex V expression | Nucleoside analogues | Remdesivir | Bradycardia, QT prologation, CA | 9 μM | HiPSC-CMs | 2.5 μM | 3 d | [86] |
OXPHOS | Downregulation of complex V expression | Addictive drugs | Ethanol | Male C57BL/6J mice | 10% (v/v) | 12 w | [162] | ||
OXPHOS | Inhibition of OXPHOS | Anti-arrhythmic drug | Clofilium | TDP | 1 μM | - | - | - | [64] |
OXPHOS | Inhibition of OXPHOS | Antipsychotics | Aripiprazole | - | 2.24 μM | - | - | - | [64] |
OXPHOS | Inhibition of OXPHOS | TKIs | Sorafenib | Bleeding, hypertension, QT prolongation, CHF, CI, MI | 16.6 μM | HiPSC-CMs | 10 µM | 24 h | [164] |
OXPHOS | OCR reduction | NSAIDs | Acetylsalicylate | - | 0.5–10 mM | Isolated rat heart mitochondria | 5 mM | [165] | |
OXPHOS | OCR reduction | NRTIs | Zidovudine | CMP | 4 μM | H9c2 | 50 μM | 3 passages | [152] |
TMPK-overexpressing H9c2 cells | 100 µM | 24 h | [131] | ||||||
Didanosine | CMP | 12 μM | H9c2 | 50 μM | 3 passages | [152] | |||
OXPHOS | OCR reduction | Nucleoside analogues | Remdesivir | Bradycardia, QT prologation, CA | 9 μM | HiPSC-CMs | 2.5 μM | 3 d | [86] |
OXPHOS | OCR reduction | Cholesterol medications | Simvastatin | Cardiac atrophy | 0.02 μM | H9c2 | 10 μM | 24 h | [151] |
OXPHOS | OCR reduction | Analgesics | Salicylic acid | - | 0.5–10 mM | Isolated rat heart mitochondria | 5 mM | [165] | |
OXPHOS | OCR reduction | Local anesthetics | Bupivacaine (marcaine) | VF | 0.7 μM | neonatal mouse cardiomyocytes | 5 μM | [166] | |
OXPHOS | Reduction in ATP content | Anesthesia | Propofol | HF, arrhythmia | 30.13 μM | Isolated rat heart mitochondria | 300 μM | [167] | |
OXPHOS | Reduction in ATP content | Local anesthetics | Lidocaine | VF | 36 μM | - | - | - | [168] |
OXPHOS | Reduction in ATP content | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | - | 15 mg/kg | - | [158] |
OXPHOS | Reduction in ATP content | Chemotherapeutic agents | Etoposide | Hypotension | 17 μM | hiPSC-CMs | 30 μM | 48 h | [169] |
OXPHOS | Mitoxantrone | CHF, CMP, decreased LVEF, arrhythmia | 3.3 μM | [160] | |||||
OXPHOS | Reduction in ATP content | Alkylating agent | Cyclophosphamide | HMC, CMP CMP, LVD, CHF | 143 μM | Male Wistar rats (IP) | 200 mg/kg | 1 w | [170] |
Male Wistar rats (IP) | 200 mg/kg | 1 w | [171] | ||||||
OXPHOS | Reduction in ATP content | Monoclonal antibody | Trastuzumab | 2.59 mM | - | - | - | [172] | |
OXPHOS | Reduction in ATP content | TKIs | Imatinib mesylate | QT prolongation, CHF, decreased LVEF | 2.71 μM | NRVMs | 5 μM | 24 h | [91] |
Sunitinib | Decreased LVEF, QT prolongation, TdP, hypertension, HF, CMP Bleeding, hypertension, QT prolongation, CHF, CI, MI | 0.25 μM | Male SD rats (oral) | 10 mg/kg/d | 3 w | [89] | |||
Male Wistar Rats (oral) | 25 mg/kg/d | 28 d | [173] | ||||||
NRVMs | 60% of ATP was depleted at 23 µM | 24 h | [174] | ||||||
Sorafenib | 16.6 μM | Male SD rats (oral) | 10 mg/kg/d | 3 w | [89] | ||||
Regorafenib | MI; hypertension | 8.08 μM | H9c2 | 5 μM | 48 h | [90] | |||
OXPHOS | Reduction in ATP content | NSAIDs | Naproxen | - | 100 µM | Isolated rat heart mitochondria | 50 μM | 1 h | [60] |
Celecoxib | Thrombosis, MI, stroke | 3–5 µM | Isolated rat heart mitochondria | 25 μM | 1 h | [60] | |||
Diclofenac | Hypertension, arrhythmias - | 7.9 µM | Isolated rat heart mitochondria | 100 μM | 1 h | [60] | |||
- | - | - | [142] | ||||||
- | - | - | [175] | ||||||
Piroxicam | 5 µM | - | - | - | [142] | ||||
Indomethacin | Hypertension | 6 µM | - | - | - | [142] | |||
Nimesulide | - | 21.08 µM | - | - | - | [142] | |||
Meloxicam | HA, stroke | 6.55 µM | - | - | - | [142] | |||
OXPHOS | Reduction in ATP content | NRTIs | Zidovudine | CMP Bradycardia, QT prologation, CA | 4 μM | Rats (oral) | 125 mg/kg/d | 4 w | [116] |
TMPK-overexpressing H9c2 cells | Dose response curve(IC50 = 70 μM) | 4 d | [131] | ||||||
OXPHOS | Reduction in ATP content | Nucleoside analogues | Remdesivir | 9 μM | [176] | ||||
OXPHOS | Reduction in ATP content | Addictive drugs | Ethanol | Arrhythmias, angina, MI, HF | Male C57BL/6J mice | 10% (v/v) for first w, 14% (v/v) for second w, 18% (v/v) for third w, | 12 w | [162] | |
H9c2 | 184.34 mM | 24 h | [177] | ||||||
Cocaine | LQT, TdP, Hypotension, AV block, Arrhythmia, heart block, SBC, CHF, VF | 0.76–0.94 µM | H9c2 | 1.79 mM | 24 h | [177] | |||
Isolated rat heart mitochondria | 2*7.5 mg/kg/d | 7 d | [178] | ||||||
Isolated rat heart mitochondria | 2*7.5 mg/kg/d | 7 d | [179] | ||||||
OXPHOS | Reduction in ATP content | Anti-arrhythmic drug | Amiodarone | 4.65 μM | H9c2 | IC50 = 1.84 µM | 4 h | [139] | |
Dronedarone | AF, HF | 0.15–0.26 μM | H9c2 | IC50 = 0.49 µM | 4 h | [139] | |||
OXPHOS | Reduction in ATP content | β-adrenoceptor agonists | Isoproterenol | HF | 0.01 μM | Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [82] |
OXPHOS | Reduction in ATP content | Cholesterol medications | Simvastatin | Cardiac atrophy | 0.02 μM | H9c2 | 10 μM (6 h); 100 μM (24 h) | [151] | |
OXPHOS | Uncoupling of OXPHOS | TKIs | Crizotinib | QT prolongation | 0.73 μM | - | - | - | [64] |
OXPHOS | Uncoupling of OXPHOS | NSAIDs | Acetylsalicylate | - | 0.5–10 mM | Isolated rat heart mitochondria | 10 mM | [165] | |
Diclofenac | Hypertension, arrhythmias | 7.9 µM | - | - | - | [142] | |||
Piroxicam | - | 5 µM | - | - | - | [142] | |||
Indomethacin | Hypertension | 6 µM | - | - | - | [142] | |||
Nimesulide | - | 21.08 µM | - | - | - | [142] | |||
Meloxicam | HA, stroke | 6.55 µM | - | - | - | [142] | |||
tenidap | - | 8.44 µM (30525499) | - | - | - | [64] | |||
OXPHOS | Uncoupling of OXPHOS | NRTIs | Zidovudine | CMP | 4 μM | H9c2 | 50 lM | 18 h | [180] |
Didanosine | CMP | 12 μM | 50 lM | 18 h | [180] | ||||
OXPHOS | Uncoupling of OXPHOS | Addictive drugs | Ethanol | Isolated mitochondria from rabbit ventricle | 10 µM | 2 h | [181] | ||
OXPHOS | Uncoupling of OXPHOS | Anti-arrhythmic drug | Amiodarone | LQT, TdP, Hypotension, AV block, Arrhythmia, heart block, SBC, CHF, VF | 4.65 μM | Isolated rat heart mitochondria | 1 µM | [139] | |
Dronedarone | AF, HF | 0.15–0.26 μM | Isolated rat heart mitochondria | 0.1 µM | [139] | ||||
OXPHOS | Uncoupling of OXPHOS | Analgesics | Salicylic acid | - | 0.5–10 mM | Isolated rat heart mitochondria | 10 mM | [165] | |
MMP | Dissipation of MMP | Anthracyclines | DOX | CMP, MI, CHF, VA, pericarditis, myocarditis | 15.3 μM | Kunming mice (IP) | 2 mg/kg | 10 d | [102] |
KIND-2-derived cardiac cells | 0.24 μM disrupte 48.3% | 48 h | [182] | ||||||
Daunorubicin | 89 μM | Neonatal rat cardiac cells | 4 μM | 24 h | [97] | ||||
MMP | Dissipation of MMP | Chemotherapeutic agents | Cisplatin | Decreased LVEF, arrhythmias, ECA, myocarditis, CMP Hypotension | 27.54 μM | C57BL mice (IV) | 10 mg/kg/d | 1 W | [112] |
NRVMs | 200 μM | 24 h | [183] | ||||||
Etoposide | 17 μM | HiPSC-CMs | 10 μM | 48 h | [169] | ||||
As2O3 | QT prolongation TdP, CMP, tachycardia | 12.1 μM | H9c2 | 5 μM | 24 h | [184] | |||
MMP | Dissipation of MMP | Monoclonal antibody | Trastuzumab | CMP, LVD, CHF | 2.59 mM | H9c2 | 200 nM | 24 h | [185] |
MMP | Dissipation of MMP | TKIs | Imatinib mesylate | QT prolongation, CHF, decreased LVEF | 2.71 μM | NRVMs | 5 μM | 18 h | [91] |
Sunitinib | Decreased LVEF, QT prolongation, TdP, hypertension, HF, CMP | 0.25 μM | Male SD rats (oral) | 10 mg/kg/d | 3 W | [89] | |||
Regorafenib | MI; hypertension | 8.08 μM | H9c2 | 20 μM | 72 h | [90] | |||
MMP | Dissipation of MMP | NSAIDs | Diclofenac | Hypertension, arrhythmias - | 7.9 µM | - | - | [142] | |
Isolated rat heart mitochondria | 10 µg/mL | [115] | |||||||
Mitochondria isolated from mouse hearts | 10 µg/mL | [157] | |||||||
C57BL/6 mice (oral) | 15 mg/kg/D | [175] | |||||||
Immortalized human cardiomyocytes | 100 μM | [85] | |||||||
Piroxicam | 5 µM | - | - | [142] | |||||
Indomethacin | Hypertension | 6 µM | - | - | [142] | ||||
Nimesulide | - | 21.08 µM | - | - | [142] | ||||
Meloxicam | HA, stroke | 6.55 µM | - | - | [142] | ||||
Meclofenamate sodium | - | 3.55 μM | H9c2 | 5 µM (40% inhibition) | [138] | ||||
Naproxen | - | 100 µM | Isolated rat heart mitochondria | 25 μM (60 min); 100 μM (30 min) | [60] | ||||
Diclofenac | Isolated rat heart mitochondria | 50 μM | 5 min | [60] | |||||
Celecoxib | Thrombosis, MI, stroke | 3–5 µM | Isolated rat heart mitochondria | 25 μM | 5 min | [60] | |||
MMP | Dissipation of MMP | NRTIs | Zidovudine | CMP | 4 μM | TMPK-overexpressing H9c2 cells | 100 µM | 24 h | [131] |
MMP | Dissipation of MMP | Anti-arrhythmic drug | Amiodarone | LQT, TdP, Hypotension, AV block, Arrhythmia, heart block, SBC, CHF, VF | 4.65 μM | H9c2 | IC50 = 2.94 μM | 6 h | [139] |
Dronedarone | AF, HF | 0.15–0.26 μM | H9c2 | IC50 = 0.5 μM | 6 h | [139] | |||
MMP | Dissipation of MMP | β receptor blocker drugs | Propranolol | Cardiotoxicity | 0.22 μM | Isolated rat heart mitochondria | 5 µg/mL | 5 min | [119] |
Atenolol | Cardiotoxicity | 4.99 μM | Isolated rat heart mitochondria | 5 µg/mL | 5 min | [119] | |||
MMP | Dissipation of MMP | Aconitum species | Aconitum sp. | VA | 19.27 μg/ml | H9c2 | 10 μM | 24 h | [186] |
MMP | Dissipation of MMP | Cholesterol medications | Simvastatin | Cardiac atrophy | 0.02 μM | H9c2 | 10 μM | 24 h | [151] |
MMP | Dissipation of MMP | Diabetes medication | Pioglitazone | HF | 2.6 μM | Isolated rat heart mitochondria | 12.5 µg/mL | 5 min | [122] |
MMP | Dissipation of MMP | Anesthesia | Propofol | HF, arrhythmia | 30.13 μM | Isolated rat heart mitochondria | 300 μM | [167] | |
MMP | Dissipation of MMP | β-adrenoceptor agonists | Isoproterenol | HF | 0.01 μM | Isolated rat heart mitochondria | 85 mg/kg/d | 2 d | [187] |
mPTP | Increases in mPTP opening | NRTIs | Zidovudine | CMP | 4 μM | TMPK-overexpressing H9c2 cells | 100 µM | 24 h | [131] |
mPTP | Increases in mPTP opening | Chemotherapeutic agents | As2O3 | QT prolongation TdP, CMP, tachycardia | 12.1 μM | Male BALB/c mice | 2 mg/kg (14 d); 4 mg/kg (3 d) | [84] | |
mPTP | Increases in mPTP opening | Monoclonal antibody | Trastuzumab | CMP, LVD, CHF | 2.59 mM | - | - | - | [22] |
mPTP | Loss of cytochrome c | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Isolated rat heart mitochondria, subcutaneously (SC) | 2 mg/kg/w | 7 w | [188] |
mPTP | Loss of cytochrome c | Chemotherapeutic agents | Cisplatin | Decreased LVEF, arrhythmias, ECA, myocarditis, CMP | 27.54 μM | NRVMs | 200 μM | 24 h | [183] |
mPTP | Loss of cytochrome c | TKIs | Imatinib mesylate | QT prolongation, CHF, decreased LVEF | 2.71 μM | NRVMs | 5 μM | 24 h | [91] |
mPTP | Loss of cytochrome c | NRTIs | Zidovudine | CMP | 4 μM | Rats (oral) | 125 mg/kg/d | [116] | |
mPTP | Loss of cytochrome c | β receptor blocker drugs | Propranolol | Cardiotoxicity | 0.22 μM | Isolated rat heart mitochondria | 5 µg/mL | 5 min | [119] |
Atenolol | Cardiotoxicity | 4.99 μM | Isolated rat heart mitochondria | 10 µg/mL | 5 min | [119] | |||
mPTP | Loss of cytochrome c | Macrolide antibiotics | Azithromycin | Arrhythmia | 0.32–0.87 μM | Isolated rat heart mitochondria | 50 μM | [120] | |
Clarithromycin | TdP | 2.67–13.37 μM | Isolated rat heart mitochondria | 50 μM | [120] | ||||
Erythromycin | TdP | 11 μM | Isolated rat heart mitochondria | 50 μM | [120] | ||||
mPTP | Loss of cytochrome c | Diabetes medication | Pioglitazone | HF | 2.6 μM | Isolated rat heart mitochondria | 12.5 µg/mL | [122] |
Modules | Alterations | Pharmacology | Drugs | Clinical Manifestations | Cmax | Models | Dose | Time | References |
---|---|---|---|---|---|---|---|---|---|
FA oxidation | Downregulation of FA oxidation related proteins expression | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male CD-1 mice (IP) | 9 mg/kg | 1 w | [100] |
Mitoxantrone | CHF, CMP, decreased LVEF, arrhythmia | 3.3 μM | Male CD-1 mice (IP) | 6 mg/kg | 1 w | [100] | |||
FA oxidation | Downregulation of FA oxidation related proteins expression | Alkylating agent | Cyclophosphamide | HMC, CMP | 143 μM | Male Wistar rats (IP) | 200 mg/kg | 10 d | [189] |
TCA cycle | Downregulation of TCA related proteins expression | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male CD-1 mice (IP) | 9 mg/kg | 1 w | [100] |
Mitoxantrone | CHF, CMP, decreased LVEF, arrhythmia | 3.3 μM | Male CD-1 mice (IP) | 6 mg/kg | 1 w | [100] | |||
TCA cycle | Inhibition of the Krebs cycle enzyme | NSAIDs | Acetylsalicylate | - | 0.5–10 mM | Isolated rat heart mitochondria | Dose response curve | [165] | |
TCA cycle | Inhibition of the Krebs cycle enzyme | Analgesics | Salicylic acid | - | 0.5–10 mM | Isolated rat heart mitochondria | Dose response curve | [165] | |
TCA cycle | Inhibition of the Krebs cycle enzyme | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male Wistar rats (IP) | 2.5 mg/kg/2 d | 2 w | [95] |
TCA cycle | Inhibition of the Krebs cycle enzyme | Alkylating agent | Cyclophosphamide | HMC, CMP | 143 μM | Male Wistar rats (IP) | 200 mg/kg | 10 d | [124] |
Male Wistar rats (IP) | 200 mg/kg | 10 d | [111] | ||||||
TCA cycle | Inhibition of the Krebs cycle enzyme | β-adrenoceptor agonists | Isoproterenol | HF | 0.01 μM | Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [83] |
TCA cycle | Loss of Krebs cycle enzymes | Addictive drugs | Ethanol | Wistar male albino rats | 3 g/kg/d | 10 d | [190] |
Modules | Alterations | Pharmacology | Drugs | Clinical Manifestations | Cmax | Models | Dose | Time | References |
---|---|---|---|---|---|---|---|---|---|
Redox | Decrease in antioxidant enzyme level | NSAIDs | Naproxen | - | 100 µM | Isolated rat heart mitochondria | 25 μM | [60] | |
Celecoxib | Thrombosis, MI, stroke | 3–5 µM | Isolated rat heart mitochondria | 50 μM | [60] | ||||
Diclofenac | - | 3.55 μM | Isolated rat heart mitochondria | 25 μM | [60] | ||||
Redox | Decrease in antioxidant enzyme level | β-adrenoceptor agonists | Isoproterenol | HF | 0.01 μM | Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [118] |
Redox | Inhibition of antioxidant enzyme | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male Wistar rats (IP) | 2.5 mg/kg/2 d | 2 w | [95] |
Kunming mice (IP) | 2 mg/kg | 10 d | [102] | ||||||
- | - | - | [199] | ||||||
Male BALB/c mice (IP) | 5 mg/kg/w | 2 w | [200] | ||||||
Male Wistar rats (IV) | 45 mg/kg | 48 h | [203] | ||||||
Idarubicin | CMP, MI, CHF, VA, decreased LVEF | 23.22 μM | Rats (IV) | 5 mg/kg/w | 6 w | [110] | |||
Redox | Inhibition of antioxidant enzyme | Alkylating agent | Cyclophosphamide | HMC, CMP | 143 μM | Male Wistar rats | 200 mg/kg | 1 w | [170] |
Male Wistar rats (IP) | 200 mg/kg | 1 w | [171] | ||||||
Redox | Inhibition of antioxidant enzyme | Chemotherapeutic agents | Cisplatin | Decreased LVEF, arrhythmias, ECA, myocarditis, CMP | 27.54 μM | NRVMs | 200 μM | 24 h | [183] |
As2O3 | QT prolongation TdP, CMP, tachycardia | 12.1 μM | BALB/c mice (IV) | 1 mg/kg/2 d | 6 d | [204] | |||
Isolated mitochondria from H9c2 | 5 μM | 24 h | [141] | ||||||
Redox | Inhibition of antioxidant enzyme | TKIs | Sunitinib | Decreased LVEF, QT prolongation, TdP, hypertension, HF, CMP | 0.25 μM | NRVMs | 67% of GSH was oxidized at 23 µM | 24 h | [174] |
Redox | Inhibition of antioxidant enzyme | NRTIs | Zidovudine | CMP | 4 μM | Male OF1 mice (oral) | 10 mg/kg/d | 35 d | [205] |
Redox | Inhibition of antioxidant enzyme | Addictive drugs | Cocaine | Arrhythmias, angina, MI, HF | 0.76–0.94 µM | H9c2 | 1.79 mM | 24 h | [177] |
Redox | Inhibition of antioxidant enzyme | β-adrenoceptor agonists | Isoproterenol | HF | 0.01 μM | Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [83] |
Redox | ROS elevation | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Beef heart submitochondrial preparations | - | - | [206] |
- | - | - | [199] | ||||||
Daunorubicin | CMP, MI, CHF, VA, pericarditis, myocarditis | 89 μM | - | - | - | [207] | |||
Idarubicin | CMP, MI, CHF, VA, decreased LVEF | 23.22 μM | - | - | - | [207] | |||
Redox | ROS elevation | Chemotherapeutic agents | Cisplatin | Decreased LVEF, arrhythmias, ECA, myocarditis, CMP | 27.54 μM | NRVMs | 200 μM | 24 h | [183] |
Etoposide | Hypotension | 17 μM | HiPSC-CMs | 10 μM | 48 h | [169] | |||
As2O3 | QT prolongation TdP, CMP, tachycardia | 12.1 μM | Male BALB/c mice | 2 mg/kg (14 d); 4 mg/kg (7 d) | [84] | ||||
Isolated mitochondria from H9c2 | 5 μM | 24 h | [141] | ||||||
H9c2 | 5 μM | 24 h | [184] | ||||||
Redox | ROS elevation | Monoclonal antibody | Trastuzumab | CMP, LVD, CHF | 2.59 mM | H9c2 | 200 nM | 24 h | [185] |
Redox | ROS elevation | TKIs | Sorafenib | Bleeding, hypertension, QT prolongation, CHF, CI, MI | 16.6 μM | NRVMs | 4.5 µM | 10 min | [32] |
Redox | ROS elevation | NSAIDs | Diclofenac | Hypertension, arrhythmias | 3.55 μM 7.9 µM | Isolated rat heart mitochondria | 25 μM | 5 min | [60] |
H9c2 | 10 µM | 1.5 h | [157] | ||||||
Isolated rat heart mitochondria | 10 µg/mL | 1 h | [115] | ||||||
C57BL/6 mice (oral) | 15 mg/kg/d | 4 w | [175] | ||||||
Immortalized human cardiomyocytes | 100 μM | 24 h | [85] | ||||||
Naproxen | - | 100 µM | Isolated rat heart mitochondria | 25 μM | 5 min | [60] | |||
Celecoxib | Thrombosis, MI, stroke | 3–5 µM | Isolated rat heart mitochondria | 25 μM | 5 min | [60] | |||
Redox | ROS elevation | NRTIs | Zidovudine | CMP | 4 μM | H9c2 | 50 μM | 3 passages | [152] |
TMPK-overexpressing H9c2 cells | 100 µM | 24 h | [131] | ||||||
Human cardiomyocytes | 10 µM | 48 h | [198] | ||||||
Didanosine | CMP | 12 μM | H9c2 | 50 μM | 3 passages | [152] | |||
Redox | ROS elevation | Addictive drugs | Ethanol | H9c2 | 184.34 mM | 24 h | [177] | ||
Cocaine | Arrhythmias, angina, MI, HF | 0.76–0.94 µM | H9c2 | 1.79 mM | 24 h | [177] | |||
Isolated rat heart mitochondria | 2 × 7.5 mg/kg/d | 8 d | [178] | ||||||
Isolated rat heart mitochondria | 2 × 7.5 mg/kg/d | 7 d | [179] | ||||||
Redox | ROS elevation | β-adrenoceptor agonists | Isoproterenol | HF | 0.01 μM | Isolated rat heart mitochondria | 85 mg/kg/d | 2 d | [187] |
Redox | ROS elevation | β receptor blocker drugs | Propranolol | Cardiotoxicity | 0.22 μM | Isolated rat heart mitochondria | 5 µg/mL | 5 min | [119] |
Atenolol | Cardiotoxicity | 4.99 μM | Isolated rat heart mitochondria | 5 µg/mL | 30 min | [119] | |||
Macrolide antibiotics | Azithromycin | Arrhythmia | 0.32–0.87 μM | Isolated rat heart mitochondria | 25 μM | 15 min | [120] | ||
Clarithromycin | TdP | 2.67–13.37 μM | Isolated rat heart mitochondria | 25 μM | 15 min | [120] | |||
Erythromycin | TdP | 11 μM | Isolated rat heart mitochondria | 25 μM | 15 min | [120] | |||
Redox | ROS elevation | Diabetes medication | Pioglitazone | HF | 2.6 μM | Isolated rat heart mitochondria | 12.5 µg/mL | 5 min | [122] |
Redox | ROS elevation | Local anesthetics | Bupivacaine (marcaine) | VF | 0.7 μM | H9c2 | 1 mM | 24 h | [208] |
Redox | Nitrozative stress | Anthracyclines | Epirubicin | CHF | 5.68 mM | Male Wistar rats (IP) | 10 mg/kg | 10 d | [209] |
Redox | Nitrozative stress | Alkylating agent | Cyclophosphamide | HMC, CMP | 143 μM | Male Wistar rats (IP) | 200 mg/kg | 1 w | [171] |
Redox | 8OHdG adducts in mtDNA | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | SD rats (IP) | 2 mg/kg/w | 6 w | [210] |
Redox | Lipid peroxidation | Anthracyclines | DOX | CHF, decreased LVEF, ST, myocarditis, CMP | 15.3 μM | Male Wistar rats (IP) | 2.5 mg/kg/2 d | 2 w | [95] |
Male Wistar rats (IV) | 45 mg/kg | 48 h | [203] | ||||||
Daunorubicin | CMP, MI, CHF, VA, pericarditis, myocarditis | 89 μM | Male SD rats | 2.5 mg/kg/w | 5 w | [211] | |||
Idarubicin | CMP, MI, CHF, VA, decreased LVEF | 23.22 μM | Male SD rats (IV) | 5 mg/kg/w | 6 w | [110] | |||
Redox | Lipid peroxidation | Alkylating agent | Cyclophosphamide | HMC, CMP | 143 μM | Male Wistar rats | 200 mg/kg | 1 w | [170] |
Redox | Lipid peroxidation | Chemotherapeutic agents | Cisplatin | Decreased LVEF, arrhythmias, ECA, myocarditis, CMP | 27.54 μM | NRVMs | 200 μM | 24 h | [183] |
Redox | Lipid peroxidation | NSAIDs | Diclofenac | Hypertension, arrhythmias | 7.9 µM | Isolated rat heart mitochondria | 50 μM | 1 h | [60] |
Isolated rat heart mitochondria | 10 µg/mL | 1 h | [115] | ||||||
Naproxen | - | 100 µM | Isolated rat heart mitochondria | 100 μM | 1 h | [60] | |||
Celecoxib | Thrombosis, MI, stroke | 3–5 µM | Isolated rat heart mitochondria | 100 μM | 1 h | [60] | |||
Redox | Lipid peroxidation | NRTIs | Zidovudine | CMP | 4 μM | Male OF1 mice (oral) | 10 mg/kg/d | 35 d | [205] |
Redox | Lipid peroxidation | β-adrenoceptor agonists | Isoproterenol | CHF, decreased LVEF, ST, myocarditis, CMP | 0.01 μM | Rat, subcutaneously (SC) | 100 mg/kg, BID | 12 h | [118] |
Male Wistar rats (SC) | 100 mg/kg, BID | 12 h | [83] |
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Tang, X.; Wang, Z.; Hu, S.; Zhou, B. Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation. Pharmaceutics 2022, 14, 1313. https://doi.org/10.3390/pharmaceutics14071313
Tang X, Wang Z, Hu S, Zhou B. Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation. Pharmaceutics. 2022; 14(7):1313. https://doi.org/10.3390/pharmaceutics14071313
Chicago/Turabian StyleTang, Xiaoli, Zengwu Wang, Shengshou Hu, and Bingying Zhou. 2022. "Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation" Pharmaceutics 14, no. 7: 1313. https://doi.org/10.3390/pharmaceutics14071313