Mechanism of depression of brain phospholipid levels by an epileptogenic drug.
Treatment of the rat with U18666A [3 beta-(2-diethylaminoethoxy) androst-5-en-17-one HCl] resulted in development of a chronic seizure state and 20-40% reductions in the concentration of all major phospholipid in whole brain. The mechanism of the phospholipid changes was explored in the present study. Incorporation of intracerebrally injected [1,3-3H]glycerol and [32P]orthophosphate into glycerolipids was decreased by 30-40% in treated rats. U18666A added in vitro to brain slices totally blocked glycerolipid synthesis at a high drug level (10(-3) M) but stimulated incorporation into diacylglycerol, phosphatidic acid and phosphatidylinositol at a lower level (10(-4) M). When added in vitro to cell fractions from liver or brain, U18666A readily inhibited phosphatidate phosphohydrolase and the acyltransferase enzymes which convert glycerolphosphate to phosphatidic acid and which convert diacylglycerol to triacylglycerol. Fifty percent inhibition of all three enzymes occurred at drug concentrations of between 0.4 and 1.0 mM. Phosphatidate cytidylyltransferase, an enzyme important to formation of phosphatidylinositol, was comparatively resistant to inhibition. Taken together, the results indicate that the marked reduction in the concentration of brain phospholipids caused by treatment of the young rat with U18666A is likely due to decreased phospholipid synthesis secondary to inhibition of several key enzymes in glycerolipid synthesis and, particularly, to inhibition of glycerolphosphate acyltransferase and phosphatidate phosphohydrolase.
D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D003292:Convulsants / Q000494:pharmacology*; D005260:Female; D005990:Glycerol / Q000378:metabolism; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000037:antagonists & inhibitors; D008297:Male; D010743:Phospholipids / Q000032:analysis* / Q000096:biosynthesis; D010758:Phosphorus / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000736:Androstenes; D003292:Convulsants; D010743:Phospholipids; D010758:Phosphorus; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D005992:Glycerol-3-Phosphate O-Acyltransferase; D005990:Glycerol