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Lithium Transport, Mg2+ Competition, and Phospholipid Composition in Human Erythrocytes: a Multinuclear Magnetic Resonance Study

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Lithium Transport, Mg2+ Competition, and Phospholipid Composition in Human Erythrocytes: a Multinuclear Magnetic Resonance Study Loyola University Chicago Loyola eCommons Dissertations Theses and Dissertations 1992 Lithium Transport, Mg2+ Competition, and Phospholipid Composition in Human Erythrocytes: A Multinuclear Magnetic Resonance Study Aida Abraha Loyola University Chicago Follow this and additional works at: https://ecommons.luc.edu/luc_diss Part of the Chemistry Commons Recommended Citation Abraha, Aida, "Lithium Transport, Mg2+ Competition, and Phospholipid Composition in Human Erythrocytes: A Multinuclear Magnetic Resonance Study" (1992). Dissertations. 3234. https://ecommons.luc.edu/luc_diss/3234 This Dissertation is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Dissertations by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 1992 Aida Abraha Aida Abraha Loyola University of Chicago 2 LITHIUM TRANSPORT. Mg + COMPETITION, AND PHOSPHOLIPID COMPOSITION IN HUMAN ERYTHROCYTES: A MULTINUCLEAR MAGNETIC RESONANCE STUDY Using 6Li and 7Li NMR, the rate of transport of 6Li+ was faster than 7Li+ by 16.7%. Naturally occurring lithium carbonate consists of 93 % 7Li and 7% 6Li. Therefore, enriching lithium salts with 6 Li could be one way of circumventing the slow action of lithium uptake. The other possibility is using Li+ selective ionophores, such as dibenzyl-14-crown-4. Using this ionophore, the Li+ /Na+ selectivity ratios for RBC suspensions and synthetic PC vesicles were 1.47 ± 0.10 and 2.26 ± 0.07, respectively. 7Li NMR spin-lattice (T,) relaxation and 31 P NMR chemical shift measurements showed 2 that binding of Li+ and Mg + to ATP and ADP was through the phosphate moieties. 1H and 13 C NMR chemical shifts showed that there was no binding of Li+ and Mg+ to the base and ribose moieties of the nucleotides. The 7Li NMR relaxation times of Li+ /Mg2+ mixtures of ATP and ADP increased with increasing concentrations of Mg2+, suggesting competition between the two ions for adenine nucleotides. 31 P chemical shift anisotropy (CSA) values increased from 51.3 ppm for membrane alone to 69.2 and 83.7 ppm in the presence of 20 mM Mg2 + and 200 mM Lt, respectively. Upon 2 titration with Li+ and Mg ', an increase in CSA values, which was caused by motional rigidity of the phosphate groups. was observed indicating binding of these ions to the membrane. 7Li 1 T 1 ielaxation times of 5 mM Li increased from 13.9 s for membrane alone to 19.5 s in the 2 presence of 2 mM Mg '. This result is indicative of a competitive mechanism between Li+ and Mg2+ for membrane phosphate binding sites. Na+-u+ countertransport rates for 10 patients receiving lithium carbonate were significantly lower than 10 matched normals (p < 0.0025). Patients' membrane PS content and T1 relaxation times were slightly higher than normals (p < 0.10), whereas the PI content was slightly lower for patients than normals (p < 0.05). No significant difference was observed between patients and controls in PC, PE, and Sph composition and intracellular Mg2+ levels. Na+ -Li+ countertransport rates showed positive correlation with PC and PI and negative correlation with PS. These findings suggest that abnormal anionic phospholipid content of RBC membranes of bipolar patients receiving lithium carbonate results in different degrees of Lt interaction with the RBC membrane and slower rates of Na+ -Li+ countertransport. 2 LITHIUM TRANSPORT, Mg + COMPETITION, AND PHOSPHOLIPID COMPOSITION IN HUMAN ERYTHROCYTES: A MULTINUCLEAR MAGNETIC RESONANCE STUDY by AIDA ABRAHA A Dissertation Submitted to the Faculty of the Graduate School of Loyola University of Chicago in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 1992 Copyright, 1992, Aida Ahraha All rights reserved. Acknowledgement I would like to thank very much my mentor, Dr. Duarte Mota de Freitas, for all the intellectual advice, emotional support, guidance and encouragement he gave me that enabled me to finish my degree. I thank him for suggesting all the challenging but realistic projects that I was able to accomplish and present at different seminars and conferences. My deepest thanks to Dr. Patrick Henry and Dr. Bruno Jaselskis for being members of my progress committee and taking the time to read the progress reports and attend the meetings. Thanks very much for all the constructive criticisms and wonderful ideas that helped me with my projects. Special thanks to Dr. Kenneth Olson and Dr. Nega Beru for being members of my dissertation committee. Thanks to all my lab mates, Mary, Ravi, Lisa, Qinfen, Suilan and Elizabeth for all their help and attention. Special thanks to the Loyola security department for escorting me home during those late night hours. My greatest appreciation to Dr Walter Dorus, Dr Joel Silberberg, Dr. Walter Wang, Dr G. Borge, and Eileen Elenz, R. N. for the supply of blood samples from bipolar patients and normal controls. I am very grateful to the IMGIP fellowship program for the support during the first three years of my graduate work without any teaching obligations and for all the financial support they gave me to attend conferences and to buy chemicals. I would like to thank the graduate school, faculty and staff for all the assistance and generosity. Special thanks to my family and friends that were with me all the way during my good and bad times. Most of all, thanks to God for giving me the health and courage to seek me through. ii Publications A) Refereed Articles: 1) "Measurement of Lithium Transport in RBCs from Psychiatric Patients Receiving Lithium carbonate and Normal Individuals by 7Li NMR Spectroscopy", D. Mota de Freitas, J. Silberberg, M. Espanol, E. Dorus, A. Abraha, W. Dorus, E. Elenz, and W. Wang, Biol. Psychiatry 28, 415-424 (1990). 2) "Competition Between Li+ and Mg2+ for ATP and ADP in Aqueous Solution: A Multinuclear NMR and Optical Spectroscopy Study", A. Abraha, D. Mota de Freitas, M.M.C.A. Castro, and C.F.G.C. Geraldes, J. Inorg. Biochem. 42, 191-198 (1991). 3) "Nuclear Magnetic Resonance Study of Differences Between 6Li and 7Li Ions in Transport Across Human Red Blood Cell Membranes", A. Abraha, E. Dorus, and D. Mota de Freitas, Lithium 2, 118-121 (1991). 4) "Vanadate Interactions With Bovine Copper, Zinc-Superoxide Dismutase as Probed by siy NMR Spectroscopy", L. Wittenkeller, A. Abraha, R. Ramasamy, D. Mota de Freitas, L. A. Theisen and D. C. Crans, J. Am Chem. Soc. 113, 7872-7881 (1991). 5) "lonophore Induced Li+ Transport Across Human Erythrocyte Membranes in the Presence of a Background Na+ Ions", A. Abraha and D. Mota de Freitas, Lithium (in press). B) Abstracts: 1) "7Li NMR Relaxation Studies of Lt Storage and Transport in RBC", D. Mota de Freitas, M. Espanol, R. Ramasamy, A. Abraha, and L. Wittenkeller, J. lnorg. Biochem. 36, 187 (1989). 2) "Multinuclear NMR Investigation of the Competition Between Mg2+ and u+ in Human RBCs", D. Mota de Freitas, R. Ramasamy, and A. Abraha, Mag. Res. 3, 65 (1990). 3) "Elucidation of Transport Mechanisms for Alkali Cations in Human RBCs by Metal NMR", D. Mota de Freitas, A. Abraha, Q. Rong, S. Mo and L. Wittenkeller, J. Jnorg. Biochem. 43, 386 (1991). 2 4) "Competition Between Li+ and Mg + for Purine Nucleoside Di- and Triphosphates in Aqueous Solution: A Multinudear NMR Study", A.Abraha, D. Mota de Freitas, Q. Rong, M.M.C.A. Castro and C.F.G.C. Carlos, J. Inorg. Biochem., 43, 389 (1991). Ill To Adey and Ababa TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ii LIST OF PUBLICATIONS iii TABLE OF CONTENTS. v LIST OF TABLES ix LIST OF FIGURES xii LIST OF ABBREVIATIONS xiv CHAPTER I INTRODUCTION. 1 A. History of Lithium 1 B. Chemical, Physical, anc.l Pharmacological Properties of Lithium Salts . 2 C. Medical and Industrial Applications of Lithium 6 D. Techniques of Lithium Analysis 8 E. Lithium lonophores . 12 F. Modes of Action of Lithium. 19 II STATEMENT OF THE PROBLEM 30 v III EXPERIMENTAL METHODS. 34 III. l Materials 34 III. IA Reagents 34 III. lB Subjects 35 III.2 Instrumentation 35 III.2A Nuclear Magnetic Resonance Spectrometer. 35 III.2B Atomic Absorption Spectrophotometer. 39 III.2C Flame Emission Spectrophotometer. 39 III.20 UV /VIS Spectrophotometer . 39 III.2E Vapor Pressure Osmometer . 39 III.2F Hemofuge 39 III.2G Refrigerated Centrifuge. 41 III.2H pH Meter 41 III.2I Lyophilizer 41 III.2J Analytical Balance 41 III.3 Sample Preparation 42 Ill.3A Metal Nucleotide Complexes in Aqueous Solution 42 III.38 Preparation of Suspension Media 42 III.3C Li --loaded RBC 43 III.30 Preparation of Shift Reagent 43 IIl.3E Preparation of Human RBC Membranes. 44 Ill.3F Preparation of Large U nilamellar Vesicles 44 IIl.3G Extraction and Analysis of Phospholipids. 45 III.4 Data Analysis. 46 vi III.4A Determination of Mg-ATP and Mg-ADP Association Constants. 46 III.48 6Li and 7Li NMR Determination of Li+ Concentrations. 47 III.4C 7 Li, 23 Na, and 35 Cl Determination of Li+, Na+, and er Concentrations. 47 III.4D Calculation of Free and Total Mgz+ in Human RBCs. 48 IIl.4E Quantitation of Phospholipids in Human R8C Membranes Using 31 P NMR. 49 III.4F Protein Determination. 49 III.4G Statistical Analysis .. 50 IV RESULTS IV.1 Isotopic Differences Between 7Li and 6Li Ions. 51 IV.IA 7Li and 6Li NMR Spectra of Human RBCs. 51 IV.IB Viability of Human Erythrocytes Incubated with 1LiCI and 6LiCl. 57 IV.IC Effect of Dy(PPP)/· on Lt Transport Across Human R8Cs Using AA. 58 IV.2 D8-14-C-4 Induced Li+ Transport in Human Erythrocytes and PC Vesicles .
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