The effect of the microtubule inhibitor colchicine on the metabolism of 125I-low density lipoprotein (LDL) by cultured human skin fibroblasts and aortic medial cells was studied in vitro. Colchicine did not alter the binding of LDL to cell surface receptors. However, the rate of LDL endocytosis was reduced to 58% of that expected. Despite diminished endocytosis, LDL was found to accumulate within the cells to 165% of that expected, whereas the release of LDL protein degradation products into the medium was reduced to 34% of control, findings consistent with a reduced rate of intracellular LDL breakdown. Colchicine did not alter cell content of the acid protease which degrades LDL, nor did [3H]colchicine accumulate in lysosomal fractions. However, colchicine did alter the intracellular distribution of both fibroblast lysosomes and endosomes. After colchicine, lysosomes tended to accumulate in the perinuclear region, whereas endosomes were found at the cell periphery. These findings are consistent with the hypothesis that ingested LDL is less available to lysosomal enzymes in the presence of colchicine. The actions of colchicine appear to be a result of destruction of cell microtubules. Lumicolchicine, a mixture of colchicine isomers which (unlike the parent compound) does not bind to the subunit of microtubules, was without effect.
Richard E. Ostlund Jr., Barbara Pfleger, Gustav Schonfeld