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Hinkovska-Galcheva V, Treadwell T, Shillingford JM, et al. Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis. J Lipid Res. 2021;62:100089doi: 10.1016/j.jlr.2021.100089.
Hinkovska-Galcheva, V., Treadwell, T., Shillingford, J. M., Lee, A., Abe, A., Tesmer, J. J. G., & Shayman, J. A. (2021). Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis. Journal of lipid research, 62100089. https://doi.org/10.1016/j.jlr.2021.100089
Hinkovska-Galcheva, Vania, et al. "Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis." Journal of lipid research vol. 62 (2021): 100089. doi: https://doi.org/10.1016/j.jlr.2021.100089
Hinkovska-Galcheva V, Treadwell T, Shillingford JM, Lee A, Abe A, Tesmer JJG, Shayman JA. Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis. J Lipid Res. 2021 Jun 01;62:100089. doi: 10.1016/j.jlr.2021.100089. Epub 2021 Jun 01. PMID: 34087196; PMCID: PMC8243516.
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J Lipid Res. 2021 Jun 01;62:100089. doi: 10.1016/j.jlr.2021.100089. Epub 2021 Jun 01.

Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis.

Journal of lipid research

Vania Hinkovska-Galcheva, Taylour Treadwell, Jonathan M Shillingford, Angela Lee, Akira Abe, John J G Tesmer, James A Shayman

Affiliations

  1. Department of Internal Medicine, University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA.
  2. Departments of Biological Sciences and Medicinal Chemistry and Pharmacology, Purdue University, West Lafayette, IN, USA.
  3. Department of Internal Medicine, University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].

PMID: 34087196 PMCID: PMC8243516 DOI: 10.1016/j.jlr.2021.100089

Abstract

Phospholipidosis, the excessive accumulation of phospholipids within lysosomes, is a pathological response observed following exposure to many drugs across multiple therapeutic groups. A clear mechanistic understanding of the causes and implications of this form of drug toxicity has remained elusive. We previously reported the discovery and characterization of a lysosome-specific phospholipase A2 (PLA2G15) and later reported that amiodarone, a known cause of drug-induced phospholipidosis, inhibits this enzyme. Here, we assayed a library of 163 drugs for inhibition of PLA2G15 to determine whether this phospholipase was the cellular target for therapeutics other than amiodarone that cause phospholipidosis. We observed that 144 compounds inhibited PLA2G15 activity. Thirty-six compounds not previously reported to cause phospholipidosis inhibited PLA2G15 with IC

Published by Elsevier Inc.

Keywords: 1-O-acylceramide; Acyltransferase; amiodarone; cationic amphiphilic drugs; drug development; drug toxicity; drug-induced phospholipidosis; high-throughput screening; lysosome; phospholipase A2 group XV

Conflict of interest statement

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. Recombinant LPLA(2) and anti-LPLA(2) monoclonal antibodies are licensed to Echelon B

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