Potent intracellular oxidative stress exerted by the carcinogen 4-nitroquinoline-N-oxide.
Oxidative stress exerted by superoxide-generating (redox-cycling) agents such as paraquat triggers the soxRS regulon of Escherichia coli. In this system, SoxR protein is the redox-sensitive activator of the soxS gene, the product of which then activates the approximately 10 promoters of this regulon. We found that 4-nitroquinoline-N-oxide (4NQO) is a powerful inducer of soxS, > 10-fold more potent than paraquat. The transcriptional induction of the soxS gene by 4NQO was tightly dependent on a functional soxR gene and on the presence of molecular oxygen, as found previously for several well characterized redox-cycling agents. Two 4NQO-related compounds were also shown to induce soxS:4-nitropyridine-N-oxide, with an efficiency only slightly less than 4NQO, and 4-hydroxyaminoquinoline-N-oxide, at approximately 50-fold lower potency than 4NQO. E. coli strains that are hypersensitive to oxidative stress (owing to deficiency in either superoxide dismutases or oxidative DNA repair enzymes) were hypersensitive to killing by 4NQO. Thus, considerable oxidative stress is induced in cells by 4NQO, which might contribute to the carcinogenic potency of this compound.
Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, Massachusetts 02115.
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D015112:4-Nitroquinoline-1-oxide / Q000031:analogs & derivatives / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins; D006861:Hydrogen Peroxide / Q000378:metabolism; D008773:Methylphenazonium Methosulfate / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D013481:Superoxides; C070724:SoxR protein, Bacteria; C070725:SoxS protein, E coli; D008773:Methylphenazonium Methosulfate; D015112:4-Nitroquinoline-1-oxide; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase