Mutagenic potency at the Na+/K+ ATPase locus correlates with cycle-dependent killing of 10T1/2 cells.

Abstract

Perturbation of DNA replication by chemical-DNA adducts produced by exposure to mutagenic/carcinogenic chemicals results in mutagenic or cytotoxic damage in the DNA. Demonstration of a correlation between cell cycle dependency of cytotoxicity and point mutation at the Na+/K+ ATPase gene could suggest that the two consequences of chemical exposure are caused by the same damage in the template DNA and that both are mediated through DNA replication-associated mechanisms. N-methyl-N'-nitro-N-nitrosoguanidine, N-ethyl-N'-nitro-N-nitrosoguanidine, 4-nitroquinoline-1-oxide, and benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide demonstrated cell cycle-related patterns of cytotoxicity in 10T1/2 cells, with maximal cell killing produced by exposure in early S phase, and were highly efficient mutagens of the Na+/K+ ATPase gene relative to their cytotoxic potential. In contrast, methyl methanesulfonate and N-acetoxy-N-2-fluorenylacetamide were maximally cytotoxic in cell populations exposed in early G1 phase and were weak mutagens of the Na+/K+ ATPase gene at comparable levels of cytotoxicity. These data suggest that mutagenic/carcinogenic chemicals that are effective at producing mutations by misreplication kill cells by a related mechanism that may be associated with the perturbation of DNA replication.