Effect of cationic amphiphilic drugs on the hydrolysis of acidic and neutral phospholipids by liver lysosomal phospholipase A.
Rat liver lysosomal phospholipase A hydrolyzes both acidic and neutral phospholipids. Numerous cationic amphiphilic drugs including imipramine, propranolol, 4,4'-bis(diethylaminoethoxy)-alpha, beta- diethyldiphenylethane and chloropromazine inhibit phospholipase A. Cationic amphiphilic drugs bind readily to acidic phospholipids but much less readily to neutral phospholipids. Formation of drug-lipid complexes is thought to be an important mechanism involved in the inhibition of lysosomal phospholipases. Therefore, we studied the effects of four cationic amphiphilic inhibitors on lysosomal phospholipase A using one acidic and two neutral phospholipid substrates. The concentration of the drugs required to produce 50% inhibition was much higher when phosphatidylinositol was used as substrate. The degradation of phosphatidylethanolamine and phosphatidylcholine was more readily inhibited by these agents than that of phosphatidylinositol. In drug-induced lipidosis, the predominance of acidic phospholipids may be due to redirection of phospholipid metabolism towards the formation of acidic phospholipids with a resultant increased delivery of these lipids to lysosomes. Based on our results, it does not appear to be due to decreased enzymatic hydrolysis of drug-acidic phospholipid complexes, at least when pure phospholipid substrates are used. Lysosomal storage of both acidic and neutral phospholipids appears to be caused by inhibition of lysosomal phospholipase action in view of the probable high intralysosomal levels of these agents.
D000818:Animals; D002746:Chlorpromazine / Q000494:pharmacology; D002847:Chromatography, Agarose; D006868:Hydrolysis; D007099:Imipramine / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000032:analysis / Q000037:antagonists & inhibitors*; D010743:Phospholipids / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity
D010743:Phospholipids; D011433:Propranolol; D010740:Phospholipases; D010741:Phospholipases A; D007099:Imipramine; D002746:Chlorpromazine