Amiodarone Drug Study Published

Luke Allen and Zeljka Korade, PhD, are first and senior authors, respectively, of a paper published in the May 20 edition of ACS Chemical Neuroscience, titled “Amiodarone Alters Cholesterol Biosynthesis through Tissue-Dependent Inhibition of Emopamil Binding Protein and Dehydrocholesterol Reductase 24.” [1]

This research was a collaboration among Dr. Korade’s laboratory in Pediatrics, Division of Inherited Metabolic Diseases; the Munroe-Meyer Institute for Genetics and Rehabilitation; and Vanderbilt University. Luke Allen and Dr. Korade responded to the following Q&A for the CHRI Research Bulletin.

Q: What is amiodarone, and what are the concerns about toxicity to patients who take this drug?

A: Amiodarone is a commonly prescribed anti-arrhythmic drug that has seen thorough use since the 1970s, though it only received FDA approval in 1985 for the treatment of arrhythmias. In 2016, amiodarone was the 198th most prescribed medication in the US. Clinically significant toxic adverse effects were observed in 1.6-2.8% of amiodarone users in a retrospective study, where duration of treatment was the major risk factor. These adverse effects include, but are not limited to, corneal microdeposits, cardiac and pulmonary toxicity, hypo- and hyper-thyroidism and liver toxicity as well as a range of neurological symptoms that manifest in both the central and peripheral nervous system.

Q: How did this question of amiodarone toxicity intersect with your expertise in studying cholesterol synthesis in the brain?

A: Amiodarone has been reported to inhibit DHCR24, which is one of the final enzymes involved in cholesterol biosynthesis. This is of particular interest in the brain due to the fact that the brain must make all of its own cholesterol from scratch and amiodarone has been shown to cross the blood brain barrier. Desmosterolosis, a developmental disorder that arises when DHCR24 is non-functional or absent is very rarely compatible with life, which illustrates the importance of this enzyme.

Q: In your study you looked at how amiodarone affects several types of cells cultured in the lab. What techniques did you use to evaluate its effects?

A: We used model cell systems representing brain, liver and kidney cell populations to investigate how each lineage responds to amiodarone. Similarly, we tested amiodarone’s effects on primary cell cultures derived from mice (neurons and astrocytes). We used shRNA gene knockdown in the brain model cell line to show that amiodarone mimics, from a biochemical standpoint, EBP inhibition in the brain. All of these models were evaluated by LC-MS/MS and GC/MS to measure the sterol content in order to assess which enzymes amiodarone was affecting in each model.

Q: What main conclusion(s) did you draw from these experiments?

A: Amiodarone inhibits two cholesterol biosynthetic enzymes, EBP and DHCR24, in a tissue-dependent manner. In neurons and astrocytes amiodarone inhibits EBP, leading to an increase in zymosterol and zymostenol, whereas in liver and kidney DHCR24 is inhibited leading to the characteristic increase in desmosterol. These elevations were also observed in the serum of patients taking amiodarone, with the exception of zymostenol.

Q: How might the results influence medical practice?

A: Monitoring the blood biochemistry with regards to cholesterol precursors in long-term amiodarone users is warranted to potentially get ahead of any of the adverse effects that are associated with long-term use of the drug.

  1. Allen LB, Genaro-Mattos TC, Anderson A, Porter NA, Mirnics K, Korade Z. Amiodarone Alters Cholesterol Biosynthesis through Tissue-Dependent Inhibition of Emopamil Binding Protein and Dehydrocholesterol Reductase 24. ACS Chem Neurosci. 2020 May 20;11(10):1413-1423. doi: 10.1021/acschemneuro.0c00042. Epub 2020 Apr 29.