Mechanism of caffeine repression of mitomycin C induced mutagenesis

Caffeine significantly repressed MMC induced $his\sp{-}$ reversion of wild type strains of Salmonella typhimurium in the standard plate reversion assay at high concentrations of MMC but not at low concentrations of MMC. The decrease in MMC induced revertants by caffeine was found to be accompanied by a decrease in the number of surviving cells. The incidence of MMC induced reversions with respect to the number of viable cells was increased by the addition of caffeine to culture media even though cell death was increased. Caffeine potentiated MMC induced cell death in S. typhimurium strains proficient in excision repair but not in excision repair deficient strains. Caffeine was more effective in wild type strains than in $recA\sp{-}$ or $polA\sp{-}$ strains. The presence of the resistance plasmid pKM101 did not alter the effectiveness of caffeine. Caffeine was found to potentiate the formation of crosslinks by MMC and to inhibit the removal of crosslinks induced by MMC in S. typhimurium strains proficient in excision repair but not in a excision repair deficient strain. The extent of the potentiation by caffeine of the formation of crosslinks in various strains correlated well with the potentiation by caffeine of MMC induced cell death. It is suggested that the potentiation by caffeine of MMC induced cell death is primarily due to the inhibition by caffeine of excision repair of crosslinks. Caffeine slightly increased the induction of recA gene expression by MMC in a wild type strain of Escherichia coli (but not in a uvrA strain) and the induction of umuC gene expression in both the wild type and uvrA strains. Among the SOS genes, recA and umuC genes are known to be involved in mutagenesis. The results of this study indicate that the apparent antimutagenic activity of caffeine on MMC induced mutations is due to the potentiation by caffeine of MMC induced cell death. Caffeine was found to potentiate MMC induced cell death primarily by inhibiting excision repair of interstrand DNA crosslinks induced by MMC. Caffeine may increase the rate of MMC induced mutations rate by inhibiting an error-free repair process (excision repair) and/or by increasing the induction of error-prone SOS functions