Item – Theses Canada

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OCLC number
46549076
Author
Rafeiro, Elizabeth,1966-
Title
An investigation of mechanisms in the pathogenesis of amiodarone-induced pulmonary toxicity.
Degree
Ph. D. -- Queen's University at Kingston, 1998
Publisher
Ottawa : National Library of Canada = Bibliothèque nationale du Canada, [1998]
Description
3 microfiches.
Notes
Includes bibliographical references.
Abstract
Amiodarone (AM) is an efficacious antidysrhythmic agent. However, its clinical use is limited by life-threatening pulmonary toxicity. The morphological effects of AM on cultured lung slices, as well as the role of free radicals and the susceptibility of the mitochondrion in AM-induced pulmonary toxicity (AIPT), were studied. The keto group of AM has been proposed to play a key role in free radical generation and AIPT. At 21 days post-dosing, hamsters treated intratracheally with 1.83 $\mu$mol of either AM or des-oxo-amiodarone (DOAM), a synthetic AM derivative lacking its keto oxygen, had increased lung weight, hydroxyproline content, and histological disease index compared to controls. Thus, DOAM possesses fibrogenic properties similar to AM, but appears to be a somewhat less potent pulmonary toxicant. Using electron spin resonance and the spin trapping agent $\alpha$-phenyl-N-t-butylnitrone (PBN), AM (2-20 mM) generated a free radical in lung and liver microsomes in vitro. The PBN-free radical adduct possessed hyperfine splitting constants (hfsc's) consistent with a carbon centred phenyl radical. In addition, both DOAM and desethylamiodarone, a major AM metabolite, generated radicals with hfsc's very similar to the AM generated radical. Many agents that initiate toxicity via a radical process induce oxidative stress, reflected by induction of antioxidant enzymes. Since assessment of oxidative stress in vivo is complicated by extrapulmonary factors, cultured hamster lung slices were used as a model system to study AIPT. Electron microscopy showed that type I alveolar cells were susceptible to damage in lung slices incubated with 200 $\mu$M AM. However, control lung slices developed elevated glutathione reductase activity, which prohibited assessment of AM's ability to induce the enzyme. AM exerted a biphasic effect (stimulation followed by inhibition) on state 4 respiration of complexes I and II in hamster lung mitochondria in vitro. Overall, this study has shown that the keto group of AM does not play a key role in AIPT, but that AM is capable of generating a free radical in lung and liver microsomes. Furthermore, the type I cell is selectively damaged in cultured lung slices incubated with AM, and AM causes dysfunction of lung mitochondria.
ISBN
0612224910
9780612224919