ABSTRACT
Addition of chlorpromazine (CPZ) of 100 microM final concentration to fragments of primordial human placenta incubated in vitro with [3H]glycerol results in the following changes in the labelling of various neutral lipids and phospholipids: (1) rapid accumulation of [3H]phosphatidic acid (PA) to a 2.31 +/- 0.12-fold (mean +/- s.d., P < 0.05) higher steady-state level within 5 min; (2) a dramatic, 5-6-fold (5.74 +/- 0.31, P < 0.01) increase in [3H]phosphatidylinositol (PI) synthesis within 5-10 min, followed by progressive PI accumulation; (3) gradual accumulation of [3H]1,2-diacylglycerol (DAG) reaching approximately 1.7-fold (1.72 +/- 0.14, P < 0.05) higher steady-state level at 30 min; and (4) an approximately 20 and 30% decrease in [3H]triacylglycerol (TG) and [3H]phosphatidylcholine (PC) formation, respectively, which begins to become evident between 10-30 min. As dose-response studies indicate, accumulations of PI and DAG are most susceptible to CPZ. They respond in the concentration range of 10-50 microM, while only higher drug concentrations (100-250 microM) affect the synthesis of PA, PC and TG significantly. Finally, dioctanoylethyleneglycol (DOEG), a structural analogue of the diacyl moiety of PA and DAG, selectively inhibits the basal synthesis (0.59 +/- 0.15, P < 0.05) as well as the CPZ-induced rise (0.49 +/- 0.11, P < 0.02) of PI. These results suggest that CPZ-induced increase in the concentrations of PI and 1,2-DAG may interfere with signal-transduction pathways in the placenta of pregnant patients treated with CPZ. Furthermore, DOEG is able to antagonize the CPZ effect which directs lipid biosynthesis towards the formation of PI.
