Modulation of mitomycin C mutagenicity on Saccharomyces cerevisiae by glutathione, 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 mutagenic/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 and on respiration. We examined the mitomycin C-induced mutagenic effects on the D7 strain of Saccharomyces cerevisiae and on its derivative mitochondrial mutant p degrees at different contents of glutathione and cytochrome P-450, molecules able to activate/detoxicate xenobiotics. The mutagenic activity of the drug was evaluated as frequency of mitotic gene conversion and reversion in different physiological conditions. The highest frequencies of reversion and especially of gene conversion were observed at the highest cytochrome P-450 contents in the D7 strain with a further increase at high glutathione level. In the respiratory-deficient strain, the highest frequency of convertants was shown at low glutathione level and lack of cytochrome P-450. These results suggest the relevance of mitochondrial functionality for the expression of genotoxic activity of this anticancer drug.
Rossi
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Istituto di Genetica, Università degli Studi di Parma, Italy. mutgen@ipruniv.cce.unipr.it
Poli
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Candi
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Buschini
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D019328:Buthionine Sulfoximine / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D005020:Ethyl Methanesulfonate / Q000494:pharmacology; D005785:Gene Conversion; D005978:Glutathione / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D006826:Hycanthone / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects*; D016685:Mitomycin / Q000633:toxicity*; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity; D019384:Nucleic Acid Synthesis Inhibitors / Q000633:toxicity; D017354:Point Mutation; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
D009153:Mutagens; D019384:Nucleic Acid Synthesis Inhibitors; D006826:Hycanthone; D019328:Buthionine Sulfoximine; D016685:Mitomycin; D003577:Cytochrome P-450 Enzyme System; D005020:Ethyl Methanesulfonate; D005978:Glutathione