Inhibition of DNA replication and repair by cadmium in mammalian cells. Protective interaction of zinc.

The effects of the treatment of cultured human and simian cells with Cadmium (Cd), a toxic and carcinogenic metal, were first assayed on macromolecular synthesis. It was observed that DNA synthesis was inhibited by Cd concentrations considerably lower than those inhibiting protein and RNA synthesis. Because of the necessary occurrence of a DNA resynthesis step during the DNA excision repair process, the consequences of the exposure of cells to Cd were ulteriorly tested on different parameters measuring DNA repair after ultraviolet (UV) damage. UV-induced unscheduled DNA synthesis (UDS) was found 2-3 times lower in Cd (4 X 10(-6) M) treated cells than in control cells for UV doses higher than 10 J/m2. DNA breaks accumulated in UV-irradiated cells during post-exposure incubation in presence of Cd, whereas they were induced only transiently in control cells irradiated with the same dose. Cd inhibited in a concentration-dependent way the recovery of RNA transcription impaired by UV-irradiation. However, at concentrations used, Cd had no significant effects on DNA size and on rRNA synthesis in unirradiated cells. Finally, Cd was shown to inhibit the repair of potentially lethal damage during a 24 h liquid holding and to increase the toxicity of UV-irradiation. The interactions between Cd and Zinc (Zn), an essential metal for many enzymatic proteins, were also analysed. Results showed that Zn, at 5 to 10 times higher concentrations, counteracts the inhibitory effects of Cd on DNA synthesis and restores, at least partially, the repair capability of cells and their survival. The possible molecular level and mechanism of action of these metals are discussed.