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biomolecules Article DiethylstilbestrolArticle Modifies the Structure of Model Membranes Diethylstilbestrol Modifies the Structure of Model Membranes andand Is Is Localized Localized Close Close to the First Carbons of the Fatty Acyl Chains AlessioAlessio Ausili, Inés Inés Rodríguez-González, Rodríguez-González, Alejandro Torrecillas, JosJoséé A.A. TeruelTeruel andand JuanJuan C.C. GGómez-Fernándezómez-Fernández ** Departamento de Bioquímica y Biología Molecular “A”, Facultad de Veterinaria, Regional Campus of Departamento de Bioquímica y Biología Molecular “A”, Facultad de Veterinaria, Regional Campus of International Excellence “Campus Mare Nostrum”, Universidad de Murcia, Apartado de Correos 4021, International Excellence “Campus Mare Nostrum”, Universidad de Murcia, Apartado de Correos 4021, E-30080-Murcia, Spain; [email protected] (A.A.); [email protected] (I.R.-G.); [email protected] (A.T.); E-30080 Murcia, Spain; [email protected] (A.A.); [email protected] (I.R.-G.); [email protected] (A.T.); [email protected] (J.A.T.) [email protected] (J.A.T.) ** Correspondence: [email protected]; Tel.: +34 +34-868-884-766;-868-884-766; Fax: +34968364147 +34-968-364-147 Abstract:Abstract: TheThe synthetic synthetic estrogen estrogen diethylstilbestrol diethylstilbestrol (DES) (DES) is is used used to to treat treat metastatic metastatic carcinomas carcinomas and and prostateprostate cancer. cancer. We We studied studied its its interaction interaction with with membranes membranes and and its its localization to to understand its its mechanismmechanism of of action action and and side-effects. side-effects. We We used used differential differential scanning scanning calorimetry calorimetry (DSC) (DSC) showing showing that DESthat fluidized DES fluidized the membrane the membrane and has and poor has solubility poor solubility in DMPC in DMPC (1,2-dimyristoyl- (1,2-dimyristoyl-sn-glycero-3-phos-sn-glycero-3- phocholine)phosphocholine) in the influid the state. fluid Using state. small-angle Using small-angle X-ray diffraction X-ray diffraction (SAXD), (SAXD),it was observed it was observedthat DES increasedthat DES increasedthe thickness the of thickness the water of layer the water between layer phospholipid between phospholipid membranes, membranes, indicating indicatingeffects on theeffects membrane on the membranesurface. DS surface.C, X-ray DSC,diffraction, X-ray and diffraction, 31P-NMR and spectroscopy31P-NMR spectroscopywere used to werestudy used the effect of DES on the Lα-to-HII phase transition, and it was observed that negative curvature of the to study the effect of DES on the Lα-to-HII phase transition, and it was observed that negative Citation: Ausili, A.; membranecurvature ofis thepromoted membrane by DES, is promoted and this byeffect DES, may and be this significant effect may to understand be significant its to action understand on mem- its Rodríguez-González, I.; Citation: Ausili, A.; braneaction enzymes. on membrane Using enzymes.the 1H-NOESY-NMR-MAS Using the 1H-NOESY-NMR-MAS technique, cross-relaxation technique, rates cross-relaxation for different ratespro- Torrecillas, A.; Teruel, J.A.; Rodríguez-González, I.; tonsfor different of DES protonswith POPC of DES (1-palmitoyl-2-oleoyl- with POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine)sn-glycero-3-phosphocholine) protons were protons calcu- Gómez-Fernández,Torrecillas, A.; Teruel, J.C. J.A.; lated,were calculated,suggesting suggestingthat the most that likely the location most likely of DE locationS in the of membrane DES in the is membrane with the main is with axis the parallel main DiethylstilbestrolGómez-Fernández, Modified J.C. the toaxis the parallel surface to and the close surface to andthe first close carbons to the first of th carbonse fatty ofacyl the chains fatty acylof POPC. chains Molecular of POPC. Moleculardynamics StructureDiethylstilbestrol of Model Modifies Membranes the and simulationsdynamics simulations were in close were agreements in close agreements with the ex withperimental the experimental results regard resultsing regarding the location the locationof DES isStructure Localized of Close Model to Membranes the First and Is in phospholipids bilayers. CarbonsLocalized of Closethe Fatty to the Acyl First Chains. Carbons of DES in phospholipids bilayers. Biomoleculesof the Fatty Acyl2021, Chains.11, x. Biomolecules 3131 11 https://doi.org/10.3390/xxxxx2021, 11, 220. https://doi.org/ Keywords:Keywords: diethylstilbestrol; membranes;membranes; P-NMR;P-NMR; H-NOESY-MAS-NMR;H-NOESY-MAS-NMR; DSC; DSC; wide-angle wide-angle X-ray X- 10.3390/biom11020220 raydiffraction diffraction (WAXD); (WAXD); SAXD SAXD Academic Editor: Jan Malínský Academic Editor: Jan Malínský Received:Received: 25 25 December December 2020 2020 Accepted:Accepted: 1 1 February February 2021 2021 1.1. Introduction Introduction Published: 4 February 2021 Published: 4 February 2021 DiethylstilbestrolDiethylstilbestrol (DES) (DES) is is a a synthetic synthetic form form of of estrogen, estrogen, a a female female hormone. hormone. Its Its name, name, established by the International Union for Pure and Applied Chemistry IUPAC, is 4-[(E)-4- Publisher’s Note: MDPI stays neu- established by the International Union for Pure and Applied Chemistry IUPAC, is 4-[(E)- Publisher’s Note: MDPI stays neutral 4-(4-hydroxyphenyl)hex-3-en-3-yl]phenol(4-hydroxyphenyl)hex-3-en-3-yl]phenol (Figure (Figure1). 1). tralwith with regard regard to to jurisdictional jurisdictionalclaims claimsin published in published maps maps and and institutional insti- tutionalaffiliations. affiliations. Copyright: © 2021 by the authors. LicenseeCopyright: MDPI,© 2021Basel, bySwitzerland. the authors. ThisLicensee article MDPI, is an open Basel, access Switzerland. article distributedThis article under is an the open terms access and articlecon- ditionsdistributed of the underCreative the Commons terms At- and conditions of the Creative Commons tribution (CC BY) license (http://cre- Attribution (CC BY) license (https:// ativecommons.org/licenses/by/4.0/). FigureFigure 1. 1. StructureStructure of of diethylstilbestrol diethylstilbestrol (DES). (DES). Protons Protons studied by 1H-NMRH-NMR are are labeled. labeled. creativecommons.org/licenses/by/ 4.0/). Biomolecules 2021, 11, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, 220. https://doi.org/10.3390/biom11020220 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, 220 2 of 17 DES consists of a drug with antiestrogenic and antiandrogenic effects, used to treat metastatic carcinomas and prostate cancer. It was widely used during some decades (1940–1970) to prevent spontaneous abortions, but it was later found that DES causes very important toxicological effects to the children exposed in the uterus to this substance, such as an increase in the risk of cancer and abnormalities in the uterus of daughters, and these effects may be seen even in the third generation [1]. Currently, this synthetic estrogen is used in rare cases, due to the existence of other drugs which cause fewer secondary effects, since DES is related to the appearance of carcinomas of the vagina and uterus in those women whose mothers received DES during their pregnancy [2,3]. DES is also an endocrine disruptor with obesogenic effects [4]. DES is an amphipathic molecule with membrane affinity, and it has been shown that it may interact with membrane enzymes such as H+-ATPases of the P-, V-, and F- types [5]. For example, it inhibits the H+-ATPase of rat liver mitochondria, interfering with the proton translocation activity of the Fo subunits [6,7]. It was also observed that DES may inhibit the Ca2+-ATPase transport system of the sarcoplasmic reticulum after insertion into the membrane, affecting the Ca2+-binding sites [8]. These inhibitory effects of DES indicate that some of its biological effects may be associated with its insertion into the membrane. Most interesting is the fact that the effects of DES may be mediated by membrane estrogen receptors. It has been shown that mice genetically engineered to lack membrane estrogen receptors do not suffer pathologies associated with exposure to DES [9]. Keeping in mind the clear association of the biological effects of DES with its insertion into membranes, it is interesting to study its interaction with model membranes and its membrane location. Given its molecular structure, it should be considered whether this molecule may alter the properties of the membranes, since it is possible that this modification might be one of the causes of its biological effects. The diverse biological activities of DES have not yet been explained from a molecular point of view. One may expect that its mechanism of action could be its interaction with hormone (estrogen) receptors since it is a synthetic structural analogue of these hormones. However, although it is true that DES could interact with the receptors of these hormones, it may interact also with membranes and may alter the activity of membrane enzymes such as H+-ATPases of the P-, V-, and F- types [5]. It is then interesting to characterize the way in which DES modulates the membrane to fully understand its molecular mechanism of action. Therefore, in this work, we studied the interaction of DES with model membranes of DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) to study its modulation of the mem- brane gel-to-fluid transition and membrane dimensions, of DEPE (1,2-dielaidoyl-sn-glycero- 3-phosphoethanolamine) to study its influence on membrane curvature, and of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine)
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    MAGNETIC RESONANCE IN CHEMISTRY Magn. Reson. Chem. 2004; 42: 105–114 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1327 Effects of antidepressants on the conformation of phospholipid headgroups studied by solid-state NMR Jose S. Santos,1† Dong-Kuk Lee1,2 and Ayyalusamy Ramamoorthy1,2,3∗ 1 Biophysics Research Division, University of Michigan, Ann Arbor, Michigan 48109-1055, USA 2 Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA 3 Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109-1055, USA Received 10 June 2003; Revised 25 August 2003; Accepted 1 September 2003 The effect of tricyclic antidepressants (TCA) on phospholipid bilayer structure and dynamics was studied to provide insight into the mechanism of TCA-induced intracellular accumulation of lipids (known as lipidosis). Specifically we asked if the lipid–TCA interaction was TCA or lipid specific and if such physical interactions could contribute to lipidosis. These interactions were probed in multilamellar vesicles and mechanically oriented bilayers of mixed phosphatidylcholine–phosphatidylglycerol (PC–PG) phospholipids using 31Pand14N solid-state NMR techniques. Changes in bilayer architecture in the presence of TCAs were observed to be dependent on the TCA’s effective charge and steric constraints. The results further show that desipramine and imipramine evoke distinguishable changes on the membrane surface, particularly on the headgroup order, conformation and dynamics of phospholipids. Desipramine increases the disorder of the choline site at the phosphatidylcholine headgroup while leaving the conformation and dynamics of the phosphate region largely unchanged. Incorporation of imipramine changes both lipid headgroup conformation and dynamics.