Cytoplasmic dissolution of phagocytized crystalline nickel sulfide particles: a prerequisite for nuclear uptake of nickel.

The intracellular fate of particulate crystalline alpha NiS, an inducer of neoplastic transformation which is readily phagocytized by cultured cells, was compared with that of particulate amorphous NiS, which does not have these properties. Amorphous and crystalline NiS both dissolve slowly in complete medium; phagocytized alpha NiS particles remain in the cytoplasm, where they dissolve more rapidly than extracellular particles. Thus the selective phagocytosis of alpha NiS accounts for both high intracellular particle accumulation and high levels of soluble Ni relative to the surrounding medium. Since phagocytized alpha NiS particles do not enter the nucleus, dissolution in the cytoplasm may represent an activation step in carcinogenesis, forming soluble Ni which diffuses into the nucleus. Dissolution products from phagocytized alpha NiS were detected in subcellular fractions isolated from treated cells; the highest levels were found in the nuclei, mitochondria, and lysosomes. That the Ni in the subcellular fractions was dissolved is suggested by the fact that dissolution products from phagocytized alpha NiS were detected in nuclei after centrifugation on sucrose pads, which substantially reduced contamination from cytoplasmic alpha NiS particles. Cytoplasmic dissolution of alpha NiS was enhanced by prior exposure of cells to the same compound. Loss of visible particles from cells was compared with loss of total Ni by use of alpha 63 NiS particles; the particles disappeared from almost half the cells during the first 2 d of treatment, while the total radioactivity associated with the cells and the total number of cells in the monolayer remained the same. The accelerated dissolution of alpha NiS after exposure to the same particles may be due to enhancement of lysosomal enzyme activity by particle phagocytosis. A 20-30% increase in intracellular acid phosphatase activity was observed after treatment with crystalline, but not amorphous, NiS, suggesting enhanced lysosomal activity.