Amiodarone induces apoptosis of human and rat  alveolar epithelial cells in vitro

Bargout, Raed; Jankov, Aleksandar; Dincer, Erhan; Wang, Rongqi; Komodromos, Themis; Ibarra-Sunga, Olivia; Filippatos, Gerasimos; Uhal, Bruce D.

doi:10.1152/ajplung.2000.278.5.l1039

Cited by 65 publications

(76 citation statements)

References 38 publications

(47 reference statements)

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“…Thus, DEA cytotoxicity in the presence of AMD was evaluated at 3 h to avoid AMD-induced cytotoxicity. Bargout et al reported that A549 cells do not express P450 monooxygenase, which plays a role in AMD metabolism, 27) and we also confirmed that DEA was not detected in a long-period uptake study of AMD in A549 cells (data not shown). Thus, the increase of cyototoxicity by the metabolism of AMD to DEA could be negligible in A549 cells.…”

Section: Effect Of Amd On Atp Content In A549 Cellssupporting

confidence: 87%

Amiodarone Increases the Accumulation of DEA in a Human Alveolar Epithelium-Derived Cell Line

Seki

Itagaki

Kobayashi

et al. 2008

Biological & Pharmaceutical Bulletin

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Amiodarone (AMD) is a highly effective drug for the treatment of cardiac dysrhythmias.1) Clinical evidence suggests that this drug has a role in reducing the relative risk for arrhythmic or sudden death and overall mortality in survivors of myocardial infarction and in heart failure patients. 2)Among the various antiarrhythmic agents, AMD has electrophysiological effects that most closely approximate those of an ideal antiarrhythmic agent.3) Although AMD is used widely, 4) AMD-induced pulmonary toxicity (AIPT) limits the clinical use of AMD.5-7) AIPT has been clinically diagnosed in 5 to 10% of patients receiving high doses of AMD and in 1.6% of patients receiving AMD at a dose of 400 mg/d or less.8) Because of its high potential for mortality, AIPT is the adverse event of greatest concern for patients receiving AMD therapy.In humans, AMD is metabolized to N-monodesethylamiodarone (DEA), an active metabolite of AMD, by P450 (CYP) 3A.9-12) The blood concentration of DEA has been shown to be comparable with that of AMD. [13][14][15] The mechanisms of AMD-or DEA-induced cytotoxicity, including altered inflammatory mediator release, 16) phosopholipidosis promotion, 17) mitochondrial dysfunction 18) and free radical production, 19) have been extensively studied. On the other hand, the tendencies of AMD and DEA to accumulate in the lung 20) are also considered factors responsible for the initiation of AIPT, and it is possible that some mechanisms contribute to the accumulation of both compounds. The accumulation of DEA in the lung is greater than that of AMD. Adams et al. reported that the DEA concentration in lung tissue of long-term AMD-treated patients was approximately 5-hold higher than that of AMD.21) Furthermore, DEA is more cytotoxic than AMD in lung cells 16) and in non-pulmonary cell types. 22)Thus, it is important to elucidate the transport mechanisms of DEA in the lung. However, the transport mechanisms of DEA as well as those of AMD have not been investigated in detail. It has been reported that DEA and AMD inhibited the transport of digoxin by human MDR1 cDNA-transfected LLC-PK 1 cells, 23) but it is unclear whether P-glycoprotein (Pgp) recognizes DEA and AMD as a substrate.Previously, we demonstrated that DEA accumulation was increased under an ATP-depleted condition in Caco-2 cells and that triiodothyronine (T 3 ) also increased the accumulation of DEA by Caco-2 cells. 24) In this study, to clarify the mechanism of high accumulation of DEA in the lung, we investigated the mechanism of AMD or DEA accumulation in A549 cells, a human alveolar epithelium-derived cell line. MATERIALS AND METHODSChemicals AMD and DEA were kindly supplied by Taisho Pharmaceutical (Tokyo, Japan). All other reagents were of the highest grade available and used without further purification. AMD and DEA were dissolved in methanol (1% w/v final concentration) due to their hydrophobic properties and poor solubility in water.Cell Culture A549 cells obtained from American Type Culture Collection (Rockville, MD, U.S.A.) were maintaine...

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Section: Effect Of Amd On Atp Content In A549 Cellssupporting

confidence: 87%

Amiodarone Increases the Accumulation of DEA in a Human Alveolar Epithelium-Derived Cell Line

Seki

Itagaki

Kobayashi

et al. 2008

Biological & Pharmaceutical Bulletin

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“…Thus, low concentrations of AM µM) did not induce cell damage in HUVECs, while a high concentration (100 µM) of AM induced cell damage. Two reports discussed the induction of apoptosis by AM in human and rat alveolar epithelial cells in vitro 19) and in L-132 human lung epithelial cell lines. 20) In our study, treatment with AM (30 µM) for 4 hours in HUVECs did not induce any apoptotic cells.…”

Section: +mentioning

confidence: 99%

Amiodarone and N-Desethylamiodarone Enhance Endothelial Nitric Oxide Production in Human Endothelial Cells

Kishida

Nakajima

et al. 2006

Int. Heart J.

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SUMMARYAmiodarone (AM) is a potent vasodilator and exhibits diverse cardiovascular protective effects in vivo, but their underlying mechanisms remain unsettled. We investigated the effects of AM and N-desethylamiodarone (DEA), the major metabolite of AM, on endothelial nitric oxide (NO) production using cultured human umbilical vein endothelial cells (HUVECs). The release of NO was evaluated as measured by nitrite, a stable metabolite of NO, using the Griess reaction and also measured directly by a NO-selective electrode. The expression of each nitric oxide synthase (NOS) mRNA was examined by reverse transcriptase-polymerase chain reaction (RT-PCR), and the effects of AM on eNOS mRNA expression were studied by quantitative real-time RT-PCR. AM and DEA(1-30 µM) enhanced NO production in a concentration-dependent manner. DEA was capable of producing more NO than AM. L-NAME, a nonselective NOS inhibitor, EGTA, a Ca 2+ -chelating agent, and nickel, a nonspecific Ca 2+ blocker, all inhibited AM-induced NO production. However, LY294002, an Akt pathway inhibitor and SB202190, a MAP kinase inhibitor, did not significantly suppress the production. In RT-PCR analysis, only eNOS mRNA was detected. Treatment with AM for 4 hours did not show a significant increase in the expression of eNOS mRNA. AM lower than 30 µM did not induce apoptosis, net cell loss, or LDH release from cells. The present study provides the first evidence that therapeutic concentrations of AM and DEA enhance eNOS-mediated NO production without any toxic or apoptotic effects. This mechanism may underlie the cardiovascular protective effects of AM and its metabolite observed in a clinical setting. (Int Heart J 2006; 47: 85-93)

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“…These findings correlated with a marked decrease in the cellular content of glutathione, as determined by 5CMF-DA fluorescence intensity. AMD-induced apoptosis has been shown in rat thymocytes [8], human monocytes [9], and also in different nonimmune cells, including cardiomyocytes [6], alveolar epithelial cells [2], thyroid cells [5], and hepatocytes [4]. Adverse effects of AMD on cell immune responses have been reported to be mediated by phospholipase inhibition or drug-induced oxidative stress and membrane destabilization [15,10].…”

Section: Discussionmentioning

confidence: 99%

“…The antiarrhythmic effect of AMD is derived from its multichannel blocking effects, including blocking of potassium and sodium channels and beta receptor blocking [1]. On the other hand, administration is often limited by its toxic side effects (pulmonary, liver, thyroid and cardiomyocytes toxicity), and drug withdrawal is often necessary [2][3][4][5][6]. When administered at higher concentrations, AMD induces mitochondrial swelling, collapse of the mitochondrial membrane potential [7], and apoptosis [5].…”

Section: Introductionmentioning

confidence: 99%

The effect of vitamin C on amiodarone-induced toxicity in rat thymocytes

et al. 2010

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AbstractAlthough, the antiarrhythmic effect of amiodarone (AMD) is well characterized, the mechanism of its toxicity on extracardiac tissues is still poorly understood. Several antioxidants have been shown to prevent AMD-induced toxicity by antioxidant and/or non-antioxidant mechanisms. In the current study, we evaluated the possible protective effect, in vitro, of vitamin C on AMD-induced toxicity in rat thymocytes. Rat thymocytes were cultured with increasing AMD concentrations (1–20 μM) with or without vitamin C (1000 μg/ml), for 24 hours. Cells treatment with AMD resulted in a concentration-dependent increase of hypodiploid cells and a significant decrease in cellular glutathione content. Vitamin C combined with AMD significantly decreased the proportion of hypodiploid cells and markedly increased the cellular glutathione content, compared with AMD treatment alone. These results suggest that treatment with vitamin C may prevent AMD-induced toxicity in rat thymocytes by restoring cellular glutathione content.

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Amiodarone induces apoptosis of human and rat alveolar epithelial cells in vitro

Cited by 65 publications

References 38 publications

Amiodarone Increases the Accumulation of DEA in a Human Alveolar Epithelium-Derived Cell Line

Amiodarone Increases the Accumulation of DEA in a Human Alveolar Epithelium-Derived Cell Line

Amiodarone and N-Desethylamiodarone Enhance Endothelial Nitric Oxide Production in Human Endothelial Cells

The effect of vitamin C on amiodarone-induced toxicity in rat thymocytes

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