EFFECTS OF 2',3'-DIDEOXYCYTIDINE AND 2',3'-DIDEOXYCYTIDINE 5'-TRIPHOSPHATE ON PHOSPHOLIPID-METABOLISM IN PERMEABILIZED RAT HEPATOCYTES

Both 2',3'-dideoxycytidine (ddC) and 2',3'-dideoxycytidine 5'-triphosp hate (ddCTP) inhibit the synthesis of the major phospholipids phosphat idylcholine (PC) and phosphatidylethanolamine (PE) in permeabilized ra t hepatocytes. For PC, this appears to be based on competitive inhibit ion of cholinephosphotransferase (CDPcholine:1,2-diacylglycerol cholin ephosphotransferase; EC 2.7.8.2). The study was based on short-term in cubations (6-12 min) of the nucleoside/nucleotide analogs with alpha-t oxin permeabilized rat hepatocytes. At a concentration of 1 mM, ddC an d ddCTP decreased the incorporation of radiolabelled glycerol-3-phosph ate into PC by approximately 50% as compared with control. This was ac companied by a significant increase in diacylglycerol labelling. In th e presence of 1 mM CDP-ethanolamine and increasing concentrations of d dC(TP) (0.01-1 mM), the incorporation of radiolabelled glycerol-3-phos phate into PE was decreased to approximately 60% of the control value. When both PC and PE synthesis were operative, the inhibition by ddC(T P) was restricted to PC synthesis. ddC and ddCTP were found to have in hibition constants (K-i) of 496 mu M and 452 mu M, respectively, for t he inhibition of PC synthesis from CDP choline. Although the inhibitor y concentrations of the nucleoside analog and its triphosphate ester a re much higher than the in vivo plasma concentrations, the possibility is raised that the peripheral neuropathy, seen as a dose-dependent ad verse effect of ddC treatment in acquired immunodeficiency syndrome th erapy is, at least partly, caused by a perturbation of the phospholipi d constitution of neuronal membranes. (C) 1997 Elsevier Science Inc.