Amiodarone Alters Cholesterol Biosynthesis through Tissue-Dependent Inhibition of Emopamil Binding Protein and Dehydrocholesterol Reductase 24.

ACS Chemical Neuroscience
Luke B AllenZeljka Korade

Abstract

Amiodarone is prescribed for the treatment and prevention of irregular heartbeats. Although effective in clinical practice, the long-term use of amiodarone has many unwanted side effects, including cardiac, pulmonary, hepatic, and neurological toxicities. Our objective was to elucidate effects of amiodarone exposure on the cholesterol metabolism in cultured neuronal and non-neuronal cells and in individuals taking amiodarone. We observed that amiodarone increases distinct cholesterol precursors in different cell types in a dose-dependent manner. In liver and kidney cell lines, amiodarone causes increase in desmosterol levels, and in primary cortical neurons and astrocytes, amiodarone increases zymosterol, zymostenol, and 8-dehydrocholesterol (8-DHC). We conclude that amiodarone inhibits two enzymes in the pathway, emopamil binding protein (EBP) and dehydrocholesterol reductase 24 (DHCR24). Cortical neurons and astrocytes are more sensitive to amiodarone than liver and kidney cell lines. We confirmed the inhibition of EBP enzyme by analyzing the sterol intermediates in EBP-deficient Neuro2a cells versus amiodarone-treated control Neuro2a cells. To determine if the cell culture experiments have clinical relevance, we analyzed ser...Continue Reading

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Citations

Sep 11, 2020·Human & Experimental Toxicology·Wan XuLixin Shang
Feb 3, 2021·ACS Chemical Neuroscience·Keri A TallmanZeljka Korade
Oct 15, 2020·The Journal of Biological Chemistry·Laura J SharpeAndrew J Brown
Feb 3, 2021·Translational Psychiatry·Zeljka KoradeKaroly Mirnics
Jan 18, 2021·The Journal of Biological Chemistry·Laura J SharpeAndrew J Brown

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