In vivo interaction between mouse liver lysosomes and chloroquine.
Particles sedimenting at 27,000 g X 10 min (MLCQ) were separated from liver homogenates of mice injected with chloroquine (CQ). The MLCQ contained most of the drug recovered in the organ as well as 50% of the liver aryl sulphatase activity. The release of CQ from MLCQ was studied in some physicochemical conditions, and in the presence of various agents known to modify membrane composition and stability. At pH 7.4, the equilibrium between free and bound CQ depended on the dilution of the MLCQ, and the time to reach equilibrium was strongly influenced by the temperature of incubation. Several agents causing membrane disruption and lysosomal enzyme leakage, such as osmotic shock, sonication and digitonin, had little effect on the CQ release. Acid and alkaline buffers, 0.55 M KCl and 0.1% Triton X-100 caused, instead, the immediate release of most of the bound CQ. Concentrations of digitonin causing the release of aryl sulphatase activity had little effect on bound CQ, suggesting that the drug is retained in lysosomes by forces and/or structures different in nature from those retaining most of the lysosomal enzyme activity. We think that the CQ trapped in lysosomes is bound to high affinity sites in membranous structures which are particularly altered by agents known to extract peripheral proteins from biological membranes or to change the conformation of molecular structures.
Colombo
M I
MI
Bertini
F
F
D000818:Animals; D002021:Buffers / Q000494:pharmacology; D002738:Chloroquine / Q000378:metabolism / Q000494:pharmacology*; D004072:Digitonin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D013347:Subcellular Fractions / Q000032:analysis / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D014461:Ultracentrifugation
D002021:Buffers; D002738:Chloroquine; D004072:Digitonin