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Combined treatment with l-carnitine and a pan-caspase inhibitor effectively reverses amiodarone-induced injury in cultured human lung epithelial cells

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Abstract

Amiodarone is an effective class III antiarrhythmic drug, however, the pulmonary toxicity is one of the most life-threatening complications of its use. The present study was designed to determine the mechanisms underlying pulmonary toxicity of amiodarone. In cultured human lung epithelial cells A549, amiodarone caused cell injury characterized by mitochondrial membrane depolarization, ATP depletion, enhanced propidium iodide (PI) uptake and increase in the number of Annexin-V positive cells, although the population of PI-stained cells appeared earlier and was not identical to that of Annexin-V stained cells, suggesting that the apoptosis and necrosis appeared in different cells. The apoptosis was accompanied with the activation of caspase-2, -3 and -8 but not caspase-9, and reversed by these caspase inhibitors. However, the caspase inhibitors had no influence on mitochondrial membrane potential or PI uptake after exposure of A549 cells to amiodarone. In contrast, mitochondrial cofactors such as L-carnitine and acetyl-l-carnitine attenuated mitochondrial membrane depolarization, abrogated cellular ATP depletion and reversed PI uptake without affecting Annexin-V positive cells. These finding suggest that different intracellular events operate to cause apoptosis and necrosis after exposure of pulmonary epithelial cells to amiodarone.

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Authors and Affiliations

  1. Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Takahisa Yano, Masahiro Yamada, Nobuaki Egashira & Ryozo Oishi

  2. Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan

    Yoshinori Itoh

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  1. Takahisa Yano
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  2. Yoshinori Itoh
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  3. Masahiro Yamada
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  4. Nobuaki Egashira
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  5. Ryozo Oishi
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Correspondence to Takahisa Yano.

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Yano, T., Itoh, Y., Yamada, M. et al. Combined treatment with l-carnitine and a pan-caspase inhibitor effectively reverses amiodarone-induced injury in cultured human lung epithelial cells. Apoptosis 13, 543–552 (2008). https://doi.org/10.1007/s10495-008-0186-9

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  • DOI: https://doi.org/10.1007/s10495-008-0186-9

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