Molecular studies of the induction of cellular phospholipidosis by cationic amphiphilic drugs

More than 30 cationic amphiphilic drugs have been shown to cause phospholipidosis in humans, animals, and cultured cells. Evidence obtained with drug-treated rats and cultured Madin-Darby canine kidney cells grown in the presence of these agents suggests a three-step mechanism: 1) the agents enter the target cell readily: 2) they concentrate in cell lysosomes; and 3) they inhibit lysosomal phospholipases A and C. The inhibition may be direct, or it may be indirect resulting from effects on lysosomal pH. This mechanism may also be relevant to other cells and tissues, although the evidence to date has been obtained in only liver and MDCK cells.