Abstract
The effects of centrophenoxine, SaH-42348, and DH-990 on several enzymes involved in aminophospholipid biosynthesis in brain have been examined in vitro. Relatively high concentrations of centrophenoxine were required to achieve 50% inhibition of the microsomal enzymes CDP-ethanolamine:1,2-diacylglycerol ethanolaminephosphotransferase (EPT), CDP-choline:1,2-diacylglycerol cholinephosphotransferase (CPT), phosphatidyl- N-methylethanolamine N-methyltransferase (PME-NMT), and phosphatidyl- N,N-dimethylethanolamine N-methyltransferase (PDE-NMT). Intermediate concentrations of SaH-42348 inhibited CPT (IC 50 = 2.0 m m), EPT (IC 50 = 1.9 m m), PME-NMT (IC 50 = 0.19 m m), and PDE-NMT (IC 50 = 0.17 m m). Of the three drugs tested, DH-990 was the most potent inhibitor of the phospholipid-synthesizing enzymes. Phosphatidylserine decarboxylase, a mitochondrial inner-membrane enzyme [ A. K. Percy, J. F. Moore, M. A. Carson, and C. J. Waechter (1983) Arch. Biochem. Biophys. 223, 484–494 ], was virtually unaffected by the three drugs added at millimolar concentrations. Kinetic analyses indicated that the inhibitory action of DH-990 on the brain enzymes was noncompetitive with respect to all substrates. The relatively high sensitivity of CPT (IC 50 = 0.6 m m), EPT (IC 50 = 2.2 m m), PME-NMT (IC 50 = 2.5 μ m), and PDE-NMT (IC 50 = 2.5 μ m) to inhibition by DH-990 in brain microsomes suggests that this compound may be useful for cellular studies on the possible relationships between phospholipid metabolism and neurobiological functions.
Published Version
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