Y. Matsuzawa, K. Hostetler
Jun 10, 1980
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0
Influential Citations
145
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Journal
The Journal of biological chemistry
Abstract
The administration of 4,4’-bis(~e~yl~noethoxy)e,@liethyldiphenylethane to mau or animals causes phospho~pid storage in liver, spleen, and other body tissues. Chloroquine has also been shown to cause phospho~pid storage in animal tissues. In a previous study of drug-induced lipidosis in rat liver, we found that the lysosomal fraction is the intracelhrlar site of the stored phospholipid and that it contains most of tbe ehloroquine or 4,4’-bis(diethylaminoethoxyh@diethyldiphenylethane (Matsuzawa, Y., aud Hostetler, K. Y. (1980) 4 Lipid Res. 21,202-214). In this paper, we have examined the effect of these cationic ampbiphilic agents on a soluble delipidated preparation from rat liver lysosomes which contains phospholipase A and C activity. Our data show that &loroquine and 4,4’-bis(~ethyl~inoetho~)a,~-~ethyldiphenylethane are potent inhibitors of lysosomal phospbo~pase A and C activities. However, these agents do not cause substantial iuhibition of the lysosomal phospholipase A wbieh catalyzes the trausaeylation step in the synthesis of bis(monoacylglycero)phosphate, a lysosomal marker lipid which is greatly increased in this drug-induced phosphoiipidosis. The inhibition of lysosomal phospholipases A and C is reversible siuce full activity can be restored by dialysis or desalting. The mechanism of iuhibition of lysosomal phospholipases A and C by these drugs is as yet unknown and will require purification of the respective enzymes. However, our experiments clearly demonstrate direct inhibition of iysosomal phospholipases A and C chloroquine and 4,4’-bis(~ethyl~noethoxy)a,#&diethyldiphenylethane and suggest that it may be a major factor in the biochemical pathogenesis of drug-induced phospholipidosis.