Chloroquine-induced phospholipid fatty liver. Measurement of drug and lipid concentrations in rat liver lysosomes.
A method has been developed to measure the concentration of chloroquine in lysosomes isolated from the liver of rats. It employs 3H2O and [U-14C]sucrose to determine the intralysosomal water volume of purified lysosomes obtained by free flow electrophoresis. Twelve h after a single dose, the concentration of chloroquine in lysosomes was 6.3 mM and at 24 h it rose to 16.5 mM. With continued treatment, lysosomal chloroquine concentrations were 61 and 74 mM at 48 and 72 h. The lysosomal concentrations of chloroquine attained were sufficient to block intralysosomal phospholipase A1 activity. The lysosomal content of phospholipid rises 1.7-fold and 2.6-fold over that of control at 12 and 24 h, respectively. At 72 h, lysosomal phospholipid was 3.7-fold greater than that of control. Lysosomes show an increased negative surface charge with chloroquine administration which is due in part to an increased ratio of acidic to neutral phospholipids in the lysosomal membrane. The phosphatidylinositol content of lysosomes rose rapidly with chloroquine treatment and accounted for the early increase in the ratio. Bis(monoacylglycero)phosphate, an acidic phospholipid synthesized only in lysosomes, increased later in the course of chloroquine treatment and accounted for the continued increase in acidic phospholipids.
D000818:Animals; D001834:Body Water / Q000032:analysis; D002250:Carbon Radioisotopes; D002738:Chloroquine / Q000494:pharmacology*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054466:Phospholipases A1; D010743:Phospholipids / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013395:Sucrose; D014316:Tritium
D002250:Carbon Radioisotopes; D010743:Phospholipids; D014316:Tritium; D013395:Sucrose; D002738:Chloroquine; D010741:Phospholipases A; D054466:Phospholipases A1