title: The adrenal specific toxicant mitotane directly interacts with lipid membranes and alters membrane properties depending on lipid composition.
abstract: Mitotane (o,p'.-DDD) is an orphan drug approved for the treatment of adrenocortical carcinoma. The mechanisms, which are responsible for this activity of the drug, are not completely understood. It can be hypothesized that an impact of mitotane is mediated by the interaction with cellular membranes. However, an interaction of mitotane with (lipid) membranes has not yet been investigated in detail. Here, we characterized the interaction of mitotane and its main metabolite o,p'-dichlorodiphenyldichloroacetic acid (o,p'-DDA) with lipid membranes by applying a variety of biophysical approaches of nuclear magnetic resonance, electron spin resonance, and fluorescence spectroscopy. We found that mitotane and o,p'-DDA bind to lipid membranes by inserting into the lipid-water interface of the bilayer. Mitotane but not o,p'-DDA directly causes a disturbance of bilayer structure leading to an increased permeability of the membrane for polar molecules. Mitotane induced alterations of the membrane integrity required the presence of phosphatidylethanolamine and/or cholesterol. Collectively, our data for the first time characterize the impact of mitotane on the lipid membrane structure and dynamics, which may contribute to a better understanding of specific mitotane effects and side effects.
authors.affiliation: University of Leipzig, Institute of Medical Physics and Biophysics, Härtelstr. 16-18, 04107 Leipzig, Germany.
authors.forename: Holger A
authors.initials: HA
authors.lastname: Scheidt
authors.affiliation: Humboldt University Berlin, Department of Biology, Invalidenstr. 42, 10115 Berlin, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Haralampiev
authors.affiliation: University of Leipzig, Institute of Medical Physics and Biophysics, Härtelstr. 16-18, 04107 Leipzig, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Theisgen
authors.affiliation: University Hospital Würzburg, Department of Nuclear Medicine, Oberdürrbacher Straße 6, 97080 Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schirbel
authors.affiliation: University Hospital Würzburg, Department of Internal Medicine I, Endocrinology and Diabetes Unit, Oberdürrbacher Straße 6, 97080 Würzburg, Germany.
authors.forename: Silviu
authors.initials: S
authors.lastname: Sbiera
authors.affiliation: University of Leipzig, Institute of Medical Physics and Biophysics, Härtelstr. 16-18, 04107 Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Huster
authors.affiliation: University Hospital Würzburg, Department of Internal Medicine I, Endocrinology and Diabetes Unit, Oberdürrbacher Straße 6, 97080 Würzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kroiss
authors.affiliation: Humboldt University Berlin, Department of Biology, Invalidenstr. 42, 10115 Berlin, Germany. Electronic address: peter.mueller.3@rz.hu-berlin.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Müller
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects*; D001205:Ascorbic Acid / Q000378:metabolism; D001681:Biological Assay; D004578:Electron Spin Resonance Spectroscopy; D005453:Fluorescence; D008051:Lipid Bilayers / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry*; D008939:Mitotane / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity*; D009928:Organ Specificity / Q000187:drug effects; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D053835:Unilamellar Liposomes / Q000737:chemistry
chemical_list: D008051:Lipid Bilayers; D008055:Lipids; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D053835:Unilamellar Liposomes; C057561:1-palmitoyl-2-oleoylphosphatidylethanolamine; C054917:2,2-(2-chlorophenyl-4'-chlorophenyl)acetic acid; D008939:Mitotane; D001205:Ascorbic Acid; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: Fluorescent lipid; Lipid vesicles; Lipid–drug interaction; Membrane structure; Mitotane; Order parameter; Spin-labeled lipid