MODULATION OF MITOMYCIN-C MUTAGENICITY ON SACCHAROMYCES-CEREVISIAE BYGLUTATHIONE, CYTOCHROME-P-450, AND MITOCHONDRIA INTERACTIONS

It is well established that most anticancer drugs also have mutagenic effects and require metabolic activation before exerting their mutagen ic/antiblastic activity. Antitumoral compound effects strongly depend on the biochemical/physiological conditions of the tumoral cells, and especially on the activation of specific drugs metabolizing enzymes an d on respiration. We examined the mitomycin C-induced mutagenic effect s on the D7 strain of Saccharomyces cerevisiae and on its derivative m itochondrial mutant rho degrees at different contents of glutathione a nd cytochrome P-450, molecules able to activate/detoxicate xenobiotics . The mutagenic activity of the drug was evaluated as frequency of mit otic gene conversion and reversion in different physiological conditio ns. The highest frequencies of reversion and especially of gene conver sion were observed at the highest cytochrome P-450 contents in the D7 strain with a further increase at high glutathione level. In the respi ratory-deficient strain, the highest frequency of convertants was show n at low glutathione level and lack of cytochrome P-450. These results suggest the relevance of mitochondrial functionality for the expressi on of genotoxic activity of this anticancer drug.