Adaptive response in mammalian cells: crossreactivity of different pretreatments on cytotoxicity as contrasted to mutagenicity.

Pretreatment of H4 (rat hepatoma) cells for 48 hr with low nontoxic doses of alkylating agents [methyl methanesulfonate (MMS), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and N-methyl-N-nitrosourea] renders the cells more resistant to the toxic effect of these compounds. Crossreactivity for survival is also observed with the different alkylating agents tested. Pretreatment with MNNG enables the cells to be less mutated than control cultures during a subsequent challenge with high doses of this compound. However, pretreatment with MMS does not modify the mutation frequency of cells challenged with either MMS or MNNG. The adaptive response to mutagenesis is correlated with a faster and more efficient removal of O6-methylguanine in MNNG-pretreated cells as compared to control cultures, whereas the disappearance of this lesion is not modified in MMS-pretreated cells. As MMS produces less methylation at the O6 position of guanine and more methylation at the N7 position in comparison to MNNG, the results suggest that: (i) N7-methylguanine is not implicated in the adaptive response and (ii) adaptation to mutagenesis can be correlated with the amount of O6-methylguanine induced during the pretreatment. The effect of pretreatment on other O-alkylated derivatives is not known.