Cytotoxic effects of amiodarone and desethylamiodarone on human thyrocytes

Beddows, Simon; Page, Sean; Taylor, Anthony H.; McNerney, Ruth; Whitley, Guy; Johnstone, Alan P.; Nussey, Stephen

doi:10.1016/0006-2952(89)90648-5

Cited by 57 publications

(26 citation statements)

References 30 publications

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“…These authors found that AMD produced a cytotoxic effect in both thyroid (FRTL-5 cells and human thyroid follicles) and non-thyroidal cell lines (Chinese hamster ovary fibroblasts), partially independent of the iodine content of the drug. Other groups have found that the major metabolite of AMD, desethylamiodarone, has greater cytotoxic effects than AMD in a number of different cell lines including human thyrocytes (20,35,36).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Indeed, because it takes less time to exert its effect, DEA has been proposed to be a more advantageous treatment option than AM itself (12). On the negative side, DEA has been found to be more toxic towards thyroid and lung tissues than AM (13,14).…”

Section: Introductionmentioning

confidence: 99%

The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole

Elsherbiny¹,

El‐Kadi²,

Brocks

2008

J Pharm Pharm Sci

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-PURPOSE. To evaluate the metabolism of amiodarone (AM) to desethylamiodarone (DEA) by selected human and rat cytochrome P450, and the inhibitory effect of ketoconazole (KTZ). METHODS. Some important CYP isoenzymes (rat CYP1A1, 1A2, 2C6, 2C11, 2D1, 2D2, and 3A1 and human CYP1A1, 1A2, 2D6 and 3A4) were spiked with various concentrations of AM to determine the relative kinetic parameters for formation of DEA in the presence and absence of various concentrations of KTZ. RESULTS. The formation of DEA was observed when AM was exposed to each of the CYP tested, although the rates were varied. Human CYP1A1 followed by 3A4 had the highest intrinsic clearance (CLint) for DEA formation whereas in rat, CYP2D1 followed by CYP2C11 had the highest CLint. Human and rat CYP1A2 seemed to have the lowest CLint. At high concentrations of AM and KTZ, near those expected in vivo, significant inhibition of all isoforms except for rat CYP1A2 was observed. At lower concentration ranges of both drugs, the inhibitory constant was determined. At these levels, KTZ was found to potently inhibit human CYP1A1 and 3A4 and rat 2D2 and 1A1. CONCLUSION. Human CYP1A1 and 3A4 and rat CYP2D1 and 2C11 were most efficient in converting AM to DEA. For DEA formation, the in vivo administration of KTZ could inhibit other CYP isoforms besides CYP3A in human and rat.

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“…These compounds are known to interact with lipids forming indigestible complexes, stored in intracellular lysosomes (16,17). Conversion to the more toxic metabolite, desethylamiodarone, may also explain the prolonged action of the drug (18).…”

Section: Discussionmentioning

confidence: 99%

Amiodarone compared with iodine exhibits a potent and persistent inhibitory effect on TSH-stimulated cAMP production in vitro: a possible mechanism to explain amiodarone-induced hypothyroidism

Pitsiavas

Smerdely²,

Boyages³

1999

European Journal of Endocrinology

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Amiodarone (AMD) is a powerful anti-arrhythmic drug used for the treatment of a wide variety of cardiac arrhythmias and its most striking feature is its high iodine content. Thyroid dysfunction is a limiting side-effect of the drug and both AMD-induced hypothyroidism (AIH) and AMD-induced thyrotoxicosis (AIT) are reported. To examine the hypothesis that altered bioavailability of iodine is a contributing event in the pathogenesis of AIH, we compared the effects of AMD and inorganic iodine in vitro on events involved in the process of thyroid autoregulation. FRTL-5 cells and JP26 CHO cells (transfected with the human TSH receptor) were exposed to AMD or NaI in the presence of TSH, and cAMP production was measured as an indicator of cellular function. Forskolin and cholera toxin were also used to determine the possible target sites of AMD and iodide. Our results indicated that there was a difference between the effects of AMD versus those of physiological doses of iodide. The inhibitory effects of AMD occurred at lower concentrations of iodide than those seen in the NaI-treated cells. The effects of AMD were irreversible indicating a possible persistence of the Wolff-Chaikoff effect due to a constant high intracellular iodide level. The inhibitory effects of AMD (also seen at supraphysiological doses of iodide) were partially overcome by forskolin but not by cholera toxin indicating an effect on TSH receptor interactions with the other signal transduction elements such as G proteins and adenylate cyclase. The persistence of the Wolff-Chaikoff effect through loss of autoregulation may be a mechanism of the observed hypothyroidism in some patients taking AMD. The combined effects of the constant release of iodide together with the drug toxicity may be the mechanism for the observed effects.

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Cytotoxic effects of amiodarone and desethylamiodarone on human thyrocytes

Cited by 57 publications

References 30 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

The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole

Amiodarone compared with iodine exhibits a potent and persistent inhibitory effect on TSH-stimulated cAMP production in vitro: a possible mechanism to explain amiodarone-induced hypothyroidism

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