An Experimental Study and Computer Simulation of the Turnover of Choline in Erythrocytes of Patients Treated With Lithium Carbonate

Abstract

Summary.The mechanism by which choline accumulates in erythrocytes during treatment with lithium salts has been elucidated. A component of the study was a kinetic description of erythrocyte phospholipase-D, which catalyses the release of intracellular choline from phospholipids. Apparent steady-state kinetic parameters for calcium ions were determined: K^ (± SD) = 0-6 ± 0'3 mmol/1 aqueous cell volume and V^,^ (± SD) =12 + 4 iimo\/\ packed red blood cells (RBC) min"'. Competitive inhibition of the phospholipase-D by barium ions was also observed. Other information concerning choline and lithium levels and red cell life-time was obtained from the literature. Details of the kinetics were used to develop a comprehensive dynamic model of choline metabolism by erythrocytes. The scheme is as follows; phosphatidylcholine associated with high density lipoproteins exchanges with the erythrocyte membrane phospholipids, the neutral phospholipids undergo two dimensional translational and rotational motion and also flip between each layer of the bilayer thus becoming exposed to an intracellularly-located phospholipase-D, whereupon the choline is hydrolysed and released into the intracellular milieu. A choline transport protein, which is able to be inhibited by lithium, mediates the influx and efflux of choline. The differential equations that describe reactant flux in this scheme were integrated numerically and the choline accumulation profiles under various conditions of transport and enzyme inhibition are presented. Computer solution of the model, by using as input values plasma lithium levels in the upper limit of the therapeutic range, required that the red cell life-time be reduced in order to explain the previously observed negative association between choline and increasing lithium levels.The results of the computer simulations under varying initial conditions of plasma and erythrocyte lithium and choline concentrations permit, for the first time, a comprehensive description of those factors affecting erythrocyte choline levels.

Proton NMR spectroscopy of human blood plasma and red blood cells

“…. Since then, !H NMR studies of red blood cells have provided information of clinical interest as well as detailed information about the biochemistry of red blood cells (5, 6,13, [33][34][35][36][37][38][39][40][41][42][43][44][45]. NMR measurements of intact red blood cells offer unique possibilities for clinical analysis.…”

“…For example, the concentrations of freely mobile metabolites and other small molecules in the intracellular region can be determined directly, the rates of selected enzymatic processes can be measured, and intracellular pH can be determined. Clinical applications will be illustrated by the determination of choline in red blood cells (37,40,41,45)', free choline accumulates in red blood cells of manic-depressive patients taking lithium carbonate.…”

N6-methyladenosine regulates ATM expression and downstream signaling

“…ATM kinase is a major regulator of the DNA damage response, and the activation of ATM upon DNA damage involves multiple cascade reactions, including acetylation 41 , UFMylation 42 and destabilization of linker histone H1.2 32 . In this study, we confirmed the presence of m6A modifications on ATM mRNA by MeRIP.…”

Release of choline by phospholipase D and a related phosphoric diester hydrolase in human erythrocytes. 1H spin-echo n.m.r. studies

“…Although cellular phospholipid content and composition change with cell age, the levels are influenced by lipid uptake from the blood plasma and by ester exchange reactions. The uptake of PC from the plasma via high-density lipoprotein (HDL) is well documented and characterized [21]. Its incorporation in the outer leaflet of the RBC membrane occurs with a tL of about 54 h [33], followed by a flip into the inner leaflet with an estimated ti of 2 h [34,35].…”

“…A dramatic elevation in the choline concentration was observed in manic-depressive patients on lithium therapy in comparison with lithium-free patients and healthy volunteers [17][18][19][20]. Lithium ions inhibit the choline transport protein in RBC membranes, causing accumulation of choline [21]. The release of choline by a Ca2+-activated phospholipase from PC in haemolysates was first monitored using 'H spin-echo n.m.r.…”