Properties of binding sites for chloroquine in liver lysosomal membranes

Chloroquine (CQ) is an antimalarial and antirheumatic drug that accumulates in lysosomes. We purified liver lysosomal membranes of tritosomes from albino mice injected with Triton WR 1339. The membranes were used for the binding assay with CQ in 0.01 M Tris-HCl buffer (pH 7.4). This binding was satu...

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Bibliographic Details
Published inJournal of cellular physiology Vol. 137; no. 3; p. 598
Main Authors Colombo, M I, Bertini, F
Format Journal Article
LanguageEnglish
Published United States 01.12.1988
Subjects
Ammonium Chloride - pharmacology
Animals
Cations, Divalent - pharmacology
Chloroquine - metabolism
Detergents - pharmacology
Hydrogen-Ion Concentration
Intracellular Membranes - metabolism
Liver - ultrastructure
Lysosomes - metabolism
Male
Mice
Neuraminidase - pharmacology
Osmolar Concentration
Phospholipases - pharmacology
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Summary:Chloroquine (CQ) is an antimalarial and antirheumatic drug that accumulates in lysosomes. We purified liver lysosomal membranes of tritosomes from albino mice injected with Triton WR 1339. The membranes were used for the binding assay with CQ in 0.01 M Tris-HCl buffer (pH 7.4). This binding was saturable, with a KD value of 6.2 microM. To understand the nature of CQ affinity, the binding was done under conditions that alter membrane structure and composition. Changes in pH, high ionic strength, and bivalent cations reversibly decreased the binding, while the effect of non-ionic detergents was partially reversed. The cationic detergent Hyamine strongly decreased the binding, and its effect was trypsin and neuraminidase had no effect. The results indicate the existence of binding sites for CQ in liver lysosomal membranes, which were strongly affected by changes of charge in the molecules involved in the binding. The treatment with the enzymes suggests that loss of polar groups of phospholipids increases the affinity of CQ by exposing protein sites located deep in the membrane, or by permiting a closer interaction between the drug and membrane lipids. CQ lysosomotropism and other effects of CQ on the lysosomal apparatus studied by other authors may be due not only to its accumulation inside the acid milieu of the lysosomes, in the same manner as other weak bases, but also to the affinity of CQ for binding sites in the lysosomal membrane.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.1041370330