Electron microscopic demonstration of lysosomal inclusion bodies in lung, liver, lymph nodes, and blood leukocytes of patients with amiodarone pulmonary toxicity

Dake, Michael D.; Madison, J. Mark; Montgomery, Carolyn K.; Shellito, Judd E.; Hinchcliffe, Warren A.; Winkler, Marion F.; Bainton, Dorothy F.

doi:10.1016/0002-9343(85)90346-8

Cited by 114 publications

(30 citation statements)

References 26 publications

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“…These inclusion or myelin-like bodies, found in the present study in rat thyroids treated with AMD, have been detected in other tissues exposed to AMD (13,20,(24)(25)(26) and appear to increase in number with increased duration of exposure of the cell to AMD (20). One likely explanation is that inclusion bodies develop to encapsulate AMD or its metabolites to avoid further toxicity to the cell (27).…”

Section: Discussionsupporting

confidence: 62%

Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat

Pitsiavas¹,

Smerdely²,

Boyages³

1997

European Journal of Endocrinology

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Amiodarone (AMD)-induced toxicity can be a life-threatening complication which limits the use of amiodarone as an anti-arrhythmic agent. The aim of the present study was to determine the nature of AMD toxicity by comparing ultrastructural changes induced by AMD and equivalent amounts of iodide in two animal models, the Wistar and the autoimmune BB/W rat. Rats were divided into control (water), AMD-(30 mg AMD/kg) or iodide-treated (10 mg/kg) groups. Thyroids were removed at 15 weeks and processed for electron microscopy.We found that AMD induced specific ultrastructural changes of thyroid cytotoxicity in both rat models, which were distinct compared with changes induced by excess iodide alone. Specific changes included marked distortion of thyroid architecture, evidence of necrosis and apoptosis, inclusion bodies, lipofuscinogenesis and markedly dilated endoplasmic reticulum (ER). Our data indicate that AMD is directly cytotoxic to the thyroid an effect mediated by disruption of subcellular organelle function. ER dilatation is suggestive that AMD cytotoxicity may be mediated through disruption of the protein sorting pathways leading to a drug-induced form of ER storage disease. The predilection of the thyroid to AMD may be explained by the additive effects of excess iodine and AMD drug toxicity on protein sorting pathways. European Journal of Endocrinology 137 89-98

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Section: Discussionsupporting

confidence: 62%

Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat

Pitsiavas¹,

Smerdely²,

Boyages³

1997

European Journal of Endocrinology

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“…The appearance of multilamellar bodies in a variety of cell types secondary to amiodarone therapy has been well documented (Adams et al, 1985;Dake et al, 1985) and is consistent with the development of a drug-induced lipidosis. In this preliminary study of a patient population with a high incidence of amiodarone toxicity the presence of multilamellar bodies in blood neutrophils was related to a number of clinically important unwanted effects, suggesting a systemic lipidosis.…”

Section: Discussionmentioning

confidence: 78%

“…We have also demonstrated the frequent development of multilamellar inclusion bodies in a variety of tissues, including pulmonary macrophages, hepatocytes, peripheral nerve tissue, cornea and blood neutrophils, suggesting a drug-induced lipidosis (Adams et al, 1985). These morphological changes are seen not only in association with clinical adverse effects (Dake et al, 1985), but also in their absence, an observation which has led us to investigate the frequency with which multilamellar bodies appear in the neutrophils of peripheral blood samples from patients taking long-term amiodarone. Their presence or absence has been correlated with drug and metabolite concentrations in plasma and with putative lipidosis-associated adverse effects, in particular those affecting the liver and lung.…”

Section: Introductionmentioning

confidence: 99%

Peripheral neutrophil inclusions in amiodarone treated patients.

Adams¹,

Sloan²,

Morley³

et al. 1986

Brit J Clinical Pharma

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In 14 patients receiving chronic amiodarone therapy the appearance of multilamellar inclusion bodies in peripheral blood neutrophils was related to both plasma concentrations of amiodarone and its desethyl metabolite and unwanted effects of the drug. Seven of the patients had well defined inclusion bodies. In this group mean amiodarone and desethylamiodarone concentrations were significantly higher than in the remaining seven patients and all but one had unwanted effects of the drug. Of the seven patients without inclusion bodies only one, with high plasma amiodarone and desethylamiodarone concentrations, had unwanted effects of the drug. It is concluded that the appearance of multilamellar bodies in the blood neutrophils of amiodarone-treated patients may help to distinguish those patients at risk of long-term amiodarone toxicity.

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“…Amiodarone hydrochloride, known to induce phospholipidosis (Sirajudeen et al, 2002;Dake et al, 1985;Poucell et al, 1984), was purchased from ICN Biomedicals Inc. (Aurora, OH, U.S.A). Tetracycline hydrochloride and carbon tetrachloride, known to induce fatty change (Fromenty and Pessayre, 1995;Brewer, 1965;Schenker, 1976;Breen et al, 1975;Recknagel et al, 1989), were purchased from Wako Pure Chemical Co. (Osaka, Japan).…”

Section: Reference Compoundsmentioning

confidence: 99%

Investigation of a Hepatotoxicity Screening System in Primary Cell Cultures-"What Biomarkers Would Need to Be Addressed to Estimate Toxicity in Conventional and New Approaches?"-

et al. 2005

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-High throughput toxicological estimation is required for safety evaluation in the early stage of drug discovery. In this context, establishment of an in vitro screening system reflecting in vivo toxicity is demanded for earlier safety assessment. We investigated LDH release and mitochondrial respiration (WST-1 reduction assay; WST-1) to detect cytotoxicity, morphological evaluation, and proteomics for estimating the reliable and sensitive biomarkers by using rat primary hepatocytes exposed to the compounds (acetaminophen, amiodarone, tetracycline and carbon tetrachloride) that are known to induce hepatotoxicity. In LDH release, no significant difference was detected between the control and compound exposed cells after exposure for 3 or 6 hr, but a dose-dependent increase was observed after exposure for 24 hr. Regarding the WST-1 assay, a dose-dependent reduction was detected after exposure for 6 and 24 hr to all of the compounds evaluated. In the proteomics analysis, 31 candidate proteins were identified from among the 103 demonstrating altered expression spots after exposure to acetaminophen. It was concluded that the cytotoxicity was detected earlier by measuring WST-1 than by measuring LDH release because the reduction of mitochondrial respiration is an expressions of earlier toxicity for cellular function, while the measured increase in the LDH release occurs after the failure of the cell membrane. Mitochondrial respiration ability was a useful parameter for cytotoxicity in in vitro hepato-toxicity screening, as cytotoxicity can be detected during the early stage of exposure. In addition to the conventional biomarkers, several protein biomarkers which relate to oxidative stress and metabolism-regulation were detected. Further comprehensive analysis of defined proteins would be necessary to estimate the more sensitive toxicology biomarker.

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Electron microscopic demonstration of lysosomal inclusion bodies in lung, liver, lymph nodes, and blood leukocytes of patients with amiodarone pulmonary toxicity

Cited by 114 publications

References 26 publications

Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat

Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat

Peripheral neutrophil inclusions in amiodarone treated patients.

Investigation of a Hepatotoxicity Screening System in Primary Cell Cultures-"What Biomarkers Would Need to Be Addressed to Estimate Toxicity in Conventional and New Approaches?"-

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