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: Holger A Scheidt, Ivan Haralampiev, Stephan Theisgen, Andreas Schirbel, Silviu Sbiera, Daniel Huster, Matthias Kroiss, Peter Müller
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 428 Pg. 68-81 (06 15 2016) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 27002491 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Lipid Bilayers
• Lipids
• Phosphatidylcholines
• Phosphatidylethanolamines
• Unilamellar Liposomes
• 1-palmitoyl-2-oleoylphosphatidylethanolamine
• 2,2-(2-chlorophenyl-4'-chlorophenyl)acetic acid
• Mitotane
• Ascorbic Acid
• 1-palmitoyl-2-oleoylphosphatidylcholine

Topics

• Adrenal Glands (drug effects)
• Ascorbic Acid (metabolism)
• Biological Assay
• Electron Spin Resonance Spectroscopy
• Fluorescence
• Lipid Bilayers (chemistry)
• Lipids (chemistry)
• Mitotane (analogs & derivatives, chemistry, toxicity)
• Organ Specificity (drug effects)
• Phosphatidylcholines
• Phosphatidylethanolamines (chemistry)
• Proton Magnetic Resonance Spectroscopy
• Unilamellar Liposomes (chemistry)