The mutagenicity of various quinones, a class of compounds widely distributed in nature, is demonstrated in the Salmonella TA104 tester strain. The metabolic pathways by which four quinones, menadione, benzo[alpyrene 3,6-quinone, 9,10-phenanthrenequinone, and danthron, caused mutagenicity in this test system were investigated in detail as were the detoxification pathways. The two-electron reduction of these quinones by NAD(P)H-quinone oxidoreductase (DT-diaphorase) was not mutagenic, whereas the one-electron reduction, catalyzed by NADPH-cytochrome P-450 reductase, was mutagenic, except for danthron, which was only slightly mutagenic. The mutagenicity of the quinones via this pathway was found to be attributable to the generation of oxygen radicals. The cytochrome P-450 monooxygenase also played a significant role in the detoxification and bioactivation of these quinones. For example, phenanthrenequinone was converted to a nonmutagenic metabolite in a cytochrome P-450-dependent reaction, whereas danthron was converted to a highly mutagenic metabolite. These studies show the complexity of metabolic pathways involved in the mutagenicity of quinones.Quinones are widely distributed in nature, and human exposure to them is extensive. The quinones of polycyclic aromatic hydrocarbons are abundant in all burnt organic material, including automobile exhaust, cigarette smoke, and urban air particulates (1-3). Quinones are also found naturally in many of the foods we eat (4-6), and compounds containing the quinone nucleus are widely employed as antitumor agents (7, 8). Despite the magnitude of this human exposure, the pathways by which many quinones are metabolized remain poorly understood and their mutagenicity is largely untested. In a recent study, however, six naturally occurring naphthoquinones, including menadione, were shown to be mutagenic to strain TA2637 with metabolic activation (9), indicating the need for further studies.Quinones serve as substrates for a wide variety of flavoenzymes, including NADPH-cytochrome P-450 reductase, NAD(P)H-quinone oxidoreductase (DT-diaphorase), NADHcytochrome b5 reductase, and NADH-ubiquinone oxidoreductase, and can undergo either a direct two-electron reduction to the hydroquinone or a one-electron reduction to the semiquinone radical (10-13). In the presence of oxygen most semiquinones rapidly autooxidize to form the superoxide anion radical (02.) and thus regenerate the quinone (14). This redox cycling can lead to conditions of oxidative stress through the production of 02 (15) and has been invoked to explain the cytotoxic and antitumor properties of quinonoid drugs (16). We have recently demonstrated that the xanthine oxidase-dependent superoxide-generating system is mutagenic to the new Salmonella tester strain TA104 (unpublished). This finding suggested that the redox cycling of quinones might also be mutagenic, and we have tested this possibility using the TA104 strain, which is sensitive to a wide variety of oxidative mutagens (17). We have also attempted to chara...