The neuroleptic chlorpromazine inhibits the cationic and stimulates the anionic phospholipid precursor synthesis in human lymphocytes.
The widely used neuroleptic drug chlorpromazine (CPZ) influences membrane functions at the levels of ionic channels and receptors as shown. Here we show the effect of short term treatments by CPZ (30 microM), on the nucleotide-containing phospholipid precursors in human lymphocyte primary cultures. During 60 minutes incubation of the cells, the CDP-ethanolamine (CDP-EA) content was only slightly reduced (87 to 76 pmol/10(6) cells), the amount of CDP-choline (CDP-Ch) was inhibited totally (from 25 to 0 pmol) upon the treatment with 30 microM CPZ under the same conditions. It has been shown earlier, that dCTP can be used as well as CTP for biosynthesis of phospholipids. Thus, the separation of the corresponding ribo- and deoxyribo-liponucleotides was developed. CPZ almost completely inhibited the synthesis of both dCDP-EA and dCDP-Ch under the same conditions The synthesis of the activated liponucleotide precursors, can be measured by incorporation of extracellular 14C-dCyt into both dCDP-EA and dCDP-Ch, as shown earlier. While the cationic deoxyribo-liponucleotide content (dCDP-Ch, dCDP-EA) was decreased, the labelling of the anionic phospholipid precursor dCDP-diacylglycerol (dCDP-DAG) was enhanced several times, it could be labelled only in the presence of CPZ from 14C-dCyd. Thus, a principal disturbance of the membrane phospholipid synthesis is presented (i.e., inhibition of the cationic and enhancement of the anionic dCDP-DAG synthesis). This profound influence on the membrane phospholipids by chlorpromazine, might be the primary effect that contributes to the wide spectrum of CPZ effects on neuronal cells.
Staub
M
M
Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary. staub@puskin.sote.hu
Stenger
A
A
Sumeg
R
R
Spasokoukotskaja
T
T
Fairbanks
L D
LD
Simmonds
H A
HA
Keszler
G
G
D000838:Anions; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002412:Cations; D002462:Cell Membrane / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology*; D002794:Choline / Q000737:chemistry; D003845:Deoxycytosine Nucleotides / Q000737:chemistry; D004075:Diglycerides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D019856:Ethanolamine / Q000737:chemistry; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D009711:Nucleotides / Q000737:chemistry; D014066:Palatine Tonsil / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry*; D013997:Time Factors
D000838:Anions; D014150:Antipsychotic Agents; D002412:Cations; D003845:Deoxycytosine Nucleotides; D004075:Diglycerides; D009711:Nucleotides; D010743:Phospholipids; D019856:Ethanolamine; C045813:2'-deoxycytidine diphosphate; D002794:Choline; D002746:Chlorpromazine