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

Luke B. Allen, Thiago C. Genaro-Mattos, Allison Anderson, Ned A. Porter, Károly Mirnics, Zeljka Korade

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 serum samples from amiodarone users. We found that in patient serum samples containing detectable amount of amiodarone there are elevated levels of the sterol precursors zymosterol, 8-DHC, and desmosterol. This study illustrates the need for close monitoring of blood biochemistry during prolonged amiodarone use to minimize the risk of side effects.

Original languageEnglish (US)
Pages (from-to)1413-1423
Number of pages11
JournalACS Chemical Neuroscience
Volume11
Issue number10
DOIs
StatePublished - May 20 2020

Keywords

  • 8-dehydrocholesterol
  • cholesterol
  • desmosterol
  • emopamil binding protein
  • zymostenol
  • zymosterol

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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