Investigation of the role of oxidative stress in amiodarone-induced pulmonary toxicity in the hamster

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Abstract
Associated with amiodarone (AM) therapy is pneumonitis, which may progress to life-threatening pulmonary fibrosis. Although the etiology of amiodarone-induced pulmonary toxicity (AIPT) is unknown, a role for direct toxicity by oxidative stress has been proposed. We have used a single intratracheal administration of AM (1.8 mg (2.64 μmol)) to male golden Syrian hamsters to investigate the role of oxidative stress in AIPT. The antioxidant capacity of the lung was assessed following AM administration by evaluating glutathione status and antioxidant enzyme activities. The efficacy of treatment with the antioxidant agents butylated hydroxyanisole, diallyl sulfide, and N-acetylcysteine, in attenuation of AM-induced pulmonary fibrosis was also investigated. AM significantly (p < 0.05) increased the ratio of oxidized to total lung glutathione both 30 min (control, 0.93 ± 0.23%; AM, 2.06 ± 0.26%) and 120 min (control, 0.90 ± 0.21%; AM, 3.58 ± 1.34%) post administration. AM also increased activities of glutathione reductase (by 89%) 3 days post administration, and glutathione peroxidase (by 110 and 45%, respectively) and total superoxide dismutase (by 58 and 35%, respectively) both 3 and 7 days post administration. However, treatment of hamsters with butylated hydroxyanisole (150 mg∙kg−1∙day−1 s.c.) or diallyl sulfide (200 mg∙kg−1∙day−1, p.o.) for 3 days prior to AM, or treatment with N-acetylcysteine (10 mg intratracheally) 10 min prior to AM had no effect on pulmonary fibrosis 21 days post treatment, as determined by lung wet weight and hydroxyproline content, and had inconsistent effects on histologically determined disease index. The alterations in glutathione status and antioxidant enzyme activities are consistent with an oxidant mechanism for AIPT, although prior treatment with the selected antioxidant agent regimens was ineffective in attenuating lung injury.Key words: amiodarone, oxidative stress, lung, fibrosis, hamster.

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