CHLOROQUINE-3H: MECHANISM OF UPTAKE BY CHANG LIVER CELLS IN VITRO’

POLET, HERMAN: Chloroquine-3H: Mechanism of uptake by Chang liver cells in vitro. J. Phanmacol. Exp. Then. 199: 687-694, 1976. The mechanism of uptake and release of the lysosomotnopic agent chloroquine-3H (CQ-3H) in cultures of Chang (CH) liver cells was investigated. The data were correlated with the morphological effects of CQ on mammalian cells, observed by other investigators. It was found that CQ-3H accumulated rapidly into CH cells. Accumula-tion was reduced to about 10 % by NaN3 and cytochalasin B and to 3 % upon exposure to 2#{176}C.Colchicine had no effect on drug uptake. Serum albumin stimulated and serum inhibited uptake, indicating the presence of factors in the serum influencing CQ-3H uptake. Efflux of cellular CQ-3H was fast, energy independent and markedly reduced at 2#{176}C.The course of CQ-3H uptake with time, as measured in the present report, together with morphological studies of other investigators, suggests that the process of CQ uptake consists of several distinct phases occurring rapidly and succeeding each other rapidly, as follows: Influx by diffusion, adsorption to a receptor concomitant with induction of membrane-bound cytoplasmic vesicles into which CQ is trapped, followed by fusion of the vesicles with lysosomes. Only the latter process appears energy-dependent and accounts for the major accumulation of CQ in cells. CH cells grown in sucrose-containing medium accumulated 2 to 3 times more CQ-3H, apparently because of expansion of the lysosomes. Such cells respond more strongly to the inhibitory effect of CQ on DNA synthesis than control cells. Mammalian cells and malarial plasmodia have the ability to concentrate chloroquine (CQ) to levels several hundred times greater than the level in the surrounding mediu