title: Phosphoglyceride biosynthesis by brain microsomes: centrophenoxine, SaH-42-348, and DH-990 inhibit phospholipid N-methylation.
abstract: The effects of centrophenoxine, SaH-42-348, 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-42-348 inhibited CPT (IC50 = 2.0 mM), EPT (IC50 = 1.9 mM), PME-NMT (IC50 = 0.19 mM), and PDE-NMT (IC50 = 0.17 mM). 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 (IC50 = 0.6 mM), EPT (IC50 = 2.2 mM), PME-NMT (IC50 = 2.5 microM), and PDE-NMT (IC50 = 2.5 microM) 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.
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002208:Caproates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004982:Ethanolaminephosphotransferase / Q000037:antagonists & inhibitors; D005994:Glycerophosphates / Q000096:biosynthesis*; D006016:Glycolates / Q000494:pharmacology*; D007700:Kinetics; D002504:Meclofenoxate / Q000494:pharmacology*; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D008861:Microsomes / Q000201:enzymology; D050941:Phosphatidyl-N-Methylethanolamine N-Methyltransferase; D050918:Phosphatidylethanolamine N-Methyltransferase; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D002208:Caproates; D005994:Glycerophosphates; D006016:Glycolates; C012656:DH 990; D002504:Meclofenoxate; D008780:Methyltransferases; D050918:Phosphatidylethanolamine N-Methyltransferase; D050941:Phosphatidyl-N-Methylethanolamine N-Methyltransferase; D004982:Ethanolaminephosphotransferase; C100041:lifibrate