Interaction of amiodarone and desethylamiodarone with solubilized nuclear thyroid hormone receptors

The mechanisms of action of the potent antiarrhythmic drug amiodarone are unknown. However, amiodarone and its abundant metabolite, desethylamiodarone, bear a striking structural resemblance to thyroid hormones. In addition, certain cardiac electrophysiologic effects of amiodarone treatment are similar to those of hypothyroidism. These facts suggest that amiodarone or desethylamiodarone could be acting, in part, by blocking thyroid hormone action. Because thyroid hormones are known to act through nuclear receptor prqteins, the binding of amiodarone and desethylamiodarone was measured to nuclear extracts derived from human lymphocytes, bovine atrium and ventricle and rat liver.The capacity of increasing concentrations of amiodarone and desethylamiodarone nuclear extracts to block receptor binding of radiolabeled triiodothyronine (T3) in a standard in vitro competition assay was tested. Nuclear extracts demonstrated only minimal binding to amiodarone. However, all receptor preparations had substantial affinities (KD) for the desethyl analog: lymphocyte, 8.6 μM; atrium, 35.0 μM; ventricle, 26.9 μM and liver, 8.6 μM. Desethylamiodarone accumulates in very large quantities in parenchymatous organs during long-term amiodarone treatment. Taking its usual therapeutic serum level (about 4 μMor 2.7 μg/ml) as an estimate of intranuclear concentration, desethylamiodarone would partially saturate nuclear thyroid hormone receptors in several different tissues, including the heart.Thus, amiodarone treatment may exert some of its electrophysiologic effects by metabolic conversion to desethylamiodarone. This metabolite may then exclude thyroid hormone from nuclear receptor sites within the myocardium

The epigenetic landscape of renal cancer

This is an accepted manuscript of an article published by Nature in Nature Reviews: Nephrology on 28/11/2016, available online: https://doi.org/10.1038/nrneph.2016.168 The accepted version of the publication may differ from the final published version.The majority of kidney cancers are associated with mutations in the von Hippel-Lindau gene and a small proportion are associated with infrequent mutations in other well characterized tumour-suppressor genes. In the past 15 years, efforts to uncover other key genes involved in renal cancer have identified many genes that are dysregulated or silenced via epigenetic mechanisms, mainly through methylation of promoter CpG islands or dysregulation of specific microRNAs. In addition, the advent of next-generation sequencing has led to the identification of several novel genes that are mutated in renal cancer, such as PBRM1, BAP1 and SETD2, which are all involved in histone modification and nucleosome and chromatin remodelling. In this Review, we discuss how altered DNA methylation, microRNA dysregulation and mutations in histone-modifying enzymes disrupt cellular pathways in renal cancers