In vitro effects of chlorpromazine on glycerol-3-phosphate acyl transferase and 1-acylglycerol-3-phosphate acyltransferase in rat liver microsomes.

The in vitro effect of chlorpromazine on rat liver glycerol-3-phosphate acyltransferase and 1-acylglycerol-3-phosphate acyltransferase was studied. Chlorpromazine decreased glycerol-3-phosphate acyltransferase activity in a concentration-dependent manner. The inhibition was competitive with respect to palmitoyl-CoA, while non-competitive with respect to sn-glycerol-3-phosphate. Ki was determined to be approximately 0.15 mM with respect to both palmitoyl-CoA and sn-glycerol-3-phosphate. From these results, together with the inhibitory effect of amphiphilic anions and neutral detergents on the enzyme demonstrated by others, it was proposed that the hydrophobic moiety of chlorpromazine competes with acyl-CoA. The activity of 1-acylglycerol-3-phosphate acyltransferase was inhibited by excess of 1-acyl-sn-glycerol-3-phosphate. In the acceptor concentration range where the substrate inhibition was observed, chlorpromazine showed stimulatory effect on the enzyme activity. At lower concentrations of the acceptor, however, chlorpromazine produced marked inhibition of the enzyme activity. From the kinetic analysis, the inhibition was found to be uncompetitive with respect to acyl-CoA. It was found that the enzyme was more susceptible to the inhibitory action of chlorpromazine with unsaturated acyl-CoAs than with the saturated species, raising the possibility that chlorpromazine alters the molecular species composition of phosphatidic acid produced by the acylation reaction.