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[摘要]：Amiodarone (AM) is a potent antidysrhythmic agent that can cause potentially life-threatening pulmonary fibrosis, and N-desethylamiodarone (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 mu M AM and approximately doubled with 3.5 mu 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 mu M AM but more than doubled after 24-h incubation with 3.5 mu M DEA. Incubation for 24 h with 5.0 mu M DEA increased the percentage of cells that were TUNEL-positive more than six times. Incubation with AM (2.5 mu M) or DEA (1-2 mu M) for 24 h did not significantly alter angiotensinogen mRNA levels. Furthermore, angiotensin II (100 pM-1 mu 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 mu 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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