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'-triphosphate (ddCTP) inhibit the synthesis of the major phospholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in permeabilized rat hepatocytes. For PC, this appears to be based on competitive inhibition of cholinephosphotransferase (CDPcholine:1,2-diacylglycerol cholinephosphotransferase; EC 2.7.8.2). The study was based on short-term incubations (6-12 min) of the nucleoside/nucleotide analogs with alpha-toxin permeabilized rat hepatocytes. At a concentration of 1 mM, ddC and ddCTP decreased the incorporation of radiolabelled glycerol-3-phosphate into PC by approximately 50% as compared with control. This was accompanied by a significant increase in diacylglycerol labelling. In the presence of 1 mM CDP-ethanolamine and increasing concentrations of ddC(TP) (0.01-1 mM), the incorporation of radiolabelled glycerol-3-phosphate into PE was decreased to approximately 60% of the control value. When both PC and PE synthesis were operative, the inhibition by ddC(TP) was restricted to PC synthesis. ddC and ddCTP were found to have inhibition constants (K(i)) of 496 microM and 452 microM, respectively, for the inhibition of PC synthesis from CDP-choline. Although the inhibitory concentrations of the nucleoside analog and its triphosphate ester are much higher than the in vivo plasma concentrations, the possibility is raised that the peripheral neuropathy, seen as a dose-dependent adverse effect of ddC treatment in acquired immunodeficiency syndrome therapy is, at least partly, caused by a perturbation of the phospholipid constitution of neuronal membranes.
De Groote
K
K
KU Leuven, Faculty of Pharmaceutical Sciences, Department of Clinical Chemistry, Onderwijs en Navorsing, Belgium.
Naesens
L
L
Balzarini
J
J
Baes
M I
MI
Declercq
P E
PE
D000818:Animals; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D003845:Deoxycytosine Nucleotides / Q000494:pharmacology*; D054306:Dideoxynucleotides; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010713:Phosphatidylcholines / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016047:Zalcitabine / Q000494:pharmacology*
D003845:Deoxycytosine Nucleotides; D054306:Dideoxynucleotides; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; C037406:2',3'-dideoxycytidine 5'-triphosphate; D016047:Zalcitabine