Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives

Waldhauser, Katri; Török, Michael; Ha, Huy Riêm; Thomet, Urs; Konrad, Daniel; Brecht, Karin; Folláth, Ferenc; Krähenbühl, Stephan

doi:10.1124/jpet.106.108993

Cited by 105 publications

(74 citation statements)

References 38 publications

(53 reference statements)

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“…The initial induction of ann-V-positive cells was not sustained at higher concentrations of DEA, which is consistent with the marked toxicity associated with 5 M DEA, a concentration that caused an even greater proportion of the cells to undergo necrosis. These DEA results are also consistent with those of other studies (Bargout et al,2000;Waldhauser et al, 2006), in which DEA increased both apoptosis and necrosis.…”

Section: Discussionsupporting

confidence: 93%

Mechanisms of Amiodarone and Desethylamiodarone Cytotoxicity in Nontransformed Human Peripheral Lung Epithelial Cells

Mulder

Brien²,

Racz³

et al. 2010

J Pharmacol Exp Ther

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Amiodarone (AM) is a potent antidysrhythmic agent that can cause potentially life-threatening pulmonary fibrosis, and Ndesethylamiodarone (DEA), an AM metabolite, may contribute to AM toxicity. Apoptotic cell death in nontransformed human peripheral lung epithelial 1A (HPL1A) cells was assessed by annexin V-fluorescein isothiocyanate (ann-V) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and necrotic cell death was assessed by propidium iodide (PI) staining. The percentage of cells that were PI-positive increased more than six times with 20 M AM and approximately doubled with 3.5 M DEA, relative to control. The percentage of cells that were ann-V-positive decreased by more than 80% after 24-h exposure to 10 M AM but more than doubled after 24-h incubation with 3.5 M DEA. Incubation for 24 h with 5.0 M DEA increased the percentage of cells that were TUNEL-positive more than six times. Incubation with AM (2.5 M) or DEA (1-2 M) for 24 h did not significantly alter angiotensinogen mRNA levels. Furthermore, angiotensin II (100 pM-1 M) alone or in combination with AM or DEA did not alter cytotoxicity, and pretreatment with the angiotensin-converting enzyme inhibitor and antioxidant captopril (3-6 M) did not protect against AM or DEA cytotoxicity. In conclusion, AM activates primarily necrotic pathways, whereas DEA activates both necrotic and apoptotic pathways, and the renin-angiotensin system does not seem to be involved in AM or DEA cytotoxicity in HPL1A cells.

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Section: Discussionsupporting

confidence: 93%

Mechanisms of Amiodarone and Desethylamiodarone Cytotoxicity in Nontransformed Human Peripheral Lung Epithelial Cells

Mulder

Brien²,

Racz³

et al. 2010

J Pharmacol Exp Ther

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“…Midazolam was obtained as a 1 mg/ml methanolic solution from Cerilliant (Round Rock, TX (Wendt et al, 2002;Lucas et al, 2006;Waldhauser et al, 2006) or as previously described (McDonald et al, 2012). Pooled human plasma from healthy individuals, containing sodium citrate as an anticoagulant, was obtained from Innovative Research (Novi, MI).…”

Section: Methodsmentioning

confidence: 99%

P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

McDonald

Rettie

2015

Drug Metab Dispos

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In this study, IC 50 shift and time-dependent inhibition (TDI) experiments were carried out to measure the ability of amiodarone (AMIO), and its circulating human metabolites, to reversibly and irreversibly inhibit CYP1A2, CYP2C9, CYP2D6, and CYP3A4 activities in human liver microsomes. The [I] u /K i,u values were calculated and used to predict in vivo AMIO drug-drug interactions (DDIs) for pharmaceuticals metabolized by these four enzymes. Based on these values, the minor metabolite N,N-didesethylamiodarone (DDEA) is predicted to be the major cause of DDIs with xenobiotics primarily metabolized by CYP1A2, CYP2C9, or CYP3A4, while AMIO and its N-monodesethylamiodarone (MDEA) derivative are the most likely cause of interactions involving inhibition of CYP2D6 metabolism. AMIO drug interactions predicted from the reversible inhibition of the four P450 activities were found to be in good agreement with the magnitude of reported clinical DDIs with lidocaine, warfarin, metoprolol, and simvastatin. The TDI experiments showed DDEA to be a potent inactivator of CYP1A2 (K I = 0.46 mM, k inact = 0.030 minute 21 ), while MDEA was a moderate inactivator of both CYP2D6 (K I = 2.7 mM, k inact = 0.018 minute 21) and CYP3A4 (K I = 2.6 mM, k inact = 0.016 minute 21). For DDEA and MDEA, mechanism-based inactivation appears to occur through formation of a metabolic intermediate complex.Additional metabolic studies strongly suggest that CYP3A4 is the primary microsomal enzyme involved in the metabolism of AMIO to both MDEA and DDEA. In summary, these studies demonstrate both the diversity of inhibitory mechanisms with AMIO and the need to consider metabolites as the culprit in inhibitory P450-based DDIs.

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“…These changes were prevented by NAC, implicating free radicals as central mediators of AMD-induced liver injury [187]. Amidarone induced a concentration-dependent increase in cell death in HepG2 cells and isolated rat hepatocytes, accompanied by a significant decrease in respiratory control ratio and oxidation of palmitate in isolated rat liver mitochondria [188]. ROS in hepatocytes were also elevated reiterating their role in induction of cell death [188].…”

Section: Amiodarone Hepatotoxicitymentioning

confidence: 99%

“…Amidarone induced a concentration-dependent increase in cell death in HepG2 cells and isolated rat hepatocytes, accompanied by a significant decrease in respiratory control ratio and oxidation of palmitate in isolated rat liver mitochondria [188]. ROS in hepatocytes were also elevated reiterating their role in induction of cell death [188]. Studies using isolated hamster liver mitochondria showed that a concentration dependent decrease in mitochondrial membrane potential on treatment with AMD, without evidence of thiobarbituric acid-reactive substances formation, suggesting that AMD brings about its effect independent of lipid peroxidation in vitro [189].…”

Section: Amiodarone Hepatotoxicitymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives

Cited by 105 publications

References 38 publications

Mechanisms of Amiodarone and Desethylamiodarone Cytotoxicity in Nontransformed Human Peripheral Lung Epithelial Cells

Mechanisms of Amiodarone and Desethylamiodarone Cytotoxicity in Nontransformed Human Peripheral Lung Epithelial Cells

P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

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