Mutagenicity of quinones: pathways of metabolic activation and detoxification.

Abstract

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...

Role of peroxide in AC electrical field exposure effects on Friend murine erythroleukemia cells during dielectrophoretic manipulations

“…ROIs are known to cause biological damage [55][56][57][58][59] including lipid peroxidation [56], and DNA [57,58] and protein damage [55]. For example, lipid peroxidation and generation of ROIs during the processes of electrofusion and electropermeabilization have been reported [29,36,37].…”

NAD(P)H:Quinone Oxidoreductase 1 Expression in Kidney Podocytes

“…This prodrug is the prototype bioreductive alkylating agent and its activation involves the reduction of the quinone group leading to interstrand DNA crosslink formation and cell death (Sartorelli 1986;Workman and Stratford 1993). A major pathway resulting in MMC activation is catalyzed by the enzyme DT-diaphorase (NAD(P)H:quinone oxidoreductase 1; NQO1; DTD), a cytosolic two-electron reductase ubiquitously expressed (Siegel et al 1990;Ross et al 1993Ross et al ,1994Workman 1994) that is known to catalyze the biotransformation of many xenobiotics, including some that are carcinogens (phase II detoxification processes) and some that are antineoplastic agents (bioactivation processes) (Lind et al 1982;Chesis et al 1984). However, a second pathway catalyzed by the one-electron NADPH-dependent cytochrome P450 reductase has been described in individuals with no DTD activity because of a point mutation in the NQO1 gene, leading to minor antitumor efficacy and to the production of toxic semiquinone intermediates (Plumb and Workman 1994;Niedermeyer et al 1999).…”

NAD(P)H:quinone oxidoreductase 1 reduces the mutagenicity of DNA caused by NADPH:P450 reductase-activated metabolites of benzo(a)pyrene quinones

“…Firstly, the quinones are mutagenic compounds and, secondly, the mutagenicity of BP is not only caused by BPDE but also by BP-3,6-Q. The various results also support the proposed chemopreventive role for NQO1 (Lind et al, 1982;Chesis et al, 1984;O'Brien, 1991;Monks et al, 1992;Joseph and Jaiswal, 1994;Talalay et al, 1995) (Figure 4). However, a careful analysis of the mutation spectra induced by metabolites of BP-3,6-Q generated by NQOI suggests that further studies are required to attribute an exclusive chemoprevention role for NQO1.…”