Toxicity of metabolic benzo(a)pyrenediones to cultured cells and the dependence upon molecular oxygen

The three quinone metabolites of carcinogenic benzo(a)pyrene, the isomeric benzo(a)pyrenediones (6, 12; 1,6; 3,6), are toxic to cultured hamster cells at low concentrations. The reduction in cell number, observed after treatment with these metabolites, is the result of both direct cell killing and the inhibition of growth, since DNA synthesis is inhibited very early after treatment with benzo(a)pyrene 1,6-dione when little cell death has occurred. The rate of RNA synthesis was also inhibited by treatment of cells with benzo(a)pyrene 3,6-dione. These actions of the benzo(a)pyrenediones toward hamster cells can be eliminated or substantially reduced by the removal of oxygen from the growth medium and atmosphere in which the cells are incubated. In contrast, anaerobic conditions do not reduce the cytotoxicity observed with the alkylating agent ethyl methanesulfonate. These results support the hypothesis that benzo(a)pyrenediones, and other biologically active quinones, owe their activity to oxidation-reduction cycles involving quinone, hydroquinone, and molecular oxygen; the reactive reduced oxygen radicals and semiquinone radical formed during these cycles may be responsible for the observed cellular injury and inhibition of cellular processes.