Amiodarone disrupts cholesterol biosynthesis pathway and causes accumulation of circulating desmosterol by inhibiting 24-dehydrocholesterol reductase.

Autor: Simonen P; From the, Heart and Lung Center, Cardiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland., Li S; Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Minerva Foundation Institute for Medical Research, Helsinki, Finland., Chua NK; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, NSW, Australia., Lampi AM; Department of Food and Nutrition, University of Helsinki, Helsinki, Finland., Piironen V; Department of Food and Nutrition, University of Helsinki, Helsinki, Finland., Lommi J; From the, Heart and Lung Center, Cardiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland., Sinisalo J; From the, Heart and Lung Center, Cardiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland., Brown AJ; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, NSW, Australia., Ikonen E; Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Minerva Foundation Institute for Medical Research, Helsinki, Finland., Gylling H; University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Jazyk: angličtina
Zdroj: Journal of internal medicine [J Intern Med] 2020 Nov; Vol. 288 (5), pp. 560-569. Date of Electronic Publication: 2020 Jun 09.
DOI: 10.1111/joim.13095
Abstrakt: Background: We have earlier reported that amiodarone, a potent and commonly used antiarrhythmic drug increases serum desmosterol, the last precursor of cholesterol, in 20 cardiac patients by an unknown mechanism.
Objective: Here, we extended our study to a large number of cardiac patients of heterogeneous diagnoses, evaluated the effects of combining amiodarone and statins (inhibitors of cholesterol synthesis at the rate-limiting step of hydroxy-methyl-glutaryl CoA reductase) on desmosterol levels and investigated the mechanism(s) by which amiodarone interferes with the metabolism of desmosterol using in vitro studies.
Methods and Results: We report in a clinical case-control setting of 236 cardiac patients (126 with and 110 without amiodarone treatment) that amiodarone medication is accompanied by a robust increase in serum desmosterol levels independently of gender, age, body mass index, cardiac and other diseases, and the use of statins. Lipid analyses in patient samples taken before and after initiation of amiodarone therapy showed a systematic increase of desmosterol upon drug administration, strongly arguing for a direct causal link between amiodarone and desmosterol accumulation. Mechanistically, we found that amiodarone resulted in desmosterol accumulation in cultured human cells and that the compound directly inhibited the 24-dehydrocholesterol reductase (DHCR24) enzyme activity.
Conclusion: These novel findings demonstrate that amiodarone blocks the cholesterol synthesis pathway by inhibiting DHCR24, causing a robust accumulation of cellular desmosterol in cells and in the sera of amiodarone-treated patients. It is conceivable that the antiarrhythmic potential and side effects of amiodarone may in part result from inhibition of the cholesterol synthesis pathway.
(© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)
Databáze: MEDLINE
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