Inhibition of Monoacylglycerophosphate Formation by Chlorophenoxyisobutyrate and β-benzalbutyrate

Monoacylglycerophosphate is the major product formed when sn-glycerol-3-P is esterified by rat liver microsomes, palmitoyl-CoA, and albumin at pH 6.5. The effect of two hypolipidemic agents, chlorophenoxyisobutyrate and β-benzalbutyrate, on monoacylglycerophosphate synthesis was studied. Both agents (0.5 to 1.0 mm) inhibited monoacylglycerophosphate synthesis by 10 to 20%. Removal of albumin from the incubation mixture produced an effect similar to the addition of chlorophenoxyisobutyrate and β-benzalbutyrate. Palmitoyl-CoA is bound by albumin and microsomal protein. Addition of both drugs decreased binding of palmitoyl-CoA by albumin and increased microsomal-bound palmitoyl-CoA, without increasing the free palmitoyl-CoA. An increase in microsomal-bound palmitoyl-CoA above 20 nmoles per mg of protein resulted in reduced monoacylglycerophosphate formation. Therefore, both agents reduced monoacylglycerophosphate formation in part by raising the concentration of microsomal-bound palmitoyl-CoA. However, both agents inhibited the reaction in the absence of albumin and under conditions in which microsomal-bound palmitoyl-CoA was held constant. These agents had no effect on several other enzymes in the pathway of glycerolipid synthesis. Therefore, chlorophenoxyisobutyrate and β-benzalbutyrate appear to be direct inhibitors of monoacylglycerophosphate formation. This inhibition may explain their early hypolipidemic effect in vivo.