The environmental pollutant and carcinogen 3-nitrobenzanthrone induces cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase in rat lung and kidney, thereby enhancing its own genotoxicity

Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches

“…Human NQO1 in the presence of its cofactor, NADPH, reductively activates 3-NBA to the reactive intermediate N -hydroxy-3-aminobenzanthrone ( N -OH-3-ABA) (see reaction step 2 in Figure 1) that dissociates to a ion that exhibits both nitrenium and carbenium character because the positive charge is delocalized to both nitrogen and carbon sites (step 3a in Figure 1), forming DNA adducts both in vitro and in vivo (Figure 1 and Figure 2; Table 1) [15,21,48,49,50,51,52,53]. N -OH-3-ABA can be further reduced to 3-aminobenzanthrone (3-ABA; step 4 in Figure 1) [14,51,52,54].…”

“…Interestingly, 3-NBA and its amino metabolite, 3-ABA, are potent inducers of NQO1 in liver, lung and kidney of rats. Such induction finally resulted in a more than 10-fold increase in the levels of 3-NBA-DNA adducts in ex vivo incubations of 3-NBA with DNA and liver, kidney and lung cytosols isolated from these animals [50,51,53], emphasizing the importance of NQO1 in the genotoxicity of 3-NBA.…”

“…Of the CYP enzymes reducing 3-NBA, CYP1A1 and 1A2 were also found to oxidize 3-ABA to N -OH-3-ABA dissociating to the ion binding to DNA (Figure 1) [80]. In addition, CYP1A1 and 1A2 are induced in liver, lung and kidney of rats not only treated with 3-NBA, but also with 3-ABA [49,50,51,53]. DNA adduct levels increased up to 12-fold due to the induction of CYP1A1/2 in lung, kidney and liver in 3-NBA- or 3-ABA-treated rats using different routes of administration including intratracheal instillation of 3-NBA [49,50,51,53].…”

The genotoxic air pollutant 3-nitrobenzanthrone and its reactive metabolite N-hydroxy-3-aminobenzanthrone lack initiating and complete carcinogenic activity in NMRI mouse skin

“…3-NBA forms DNA adducts in vitro and in rodents in vivo after metabolic activation through reduction of the nitro group, primarily catalysed by cytosolic nitroreductases such as NAD(P)H:quinone oxidoreductase (NQO1) (Fig. 1) [31][32][33][34][35]. The uptake of 3-NBA in humans has been demonstrated by the detection of 3-aminobenzanthrone (3-ABA; Fig.…”

Asian dust storm particles induce a broad toxicological transcriptional program in human epidermal keratinocytes

“…In addition, ADSPs are mixed with locally generated environmental pollutants and may promote direct contact of these pollutants to exposed skin regions (Im et al, 2006;Kim et al, 2008). Many chemical pollutants, which may be adsorbed on ADSPs, such as dioxins and nitrobenzanthrones, can regulate mRNA expression of the transcription factor AHR (Im et al, 2006;Mimura and Fujii-Kuriyama, 2003;Stiborova et al, 2008). AHR plays an important role in the regulation of xenobiotic metabolism by, for example, controlling the expression of cytochrome P450 enzymes, but it is also important in cellular development and differentiation (Monk et al, 2003).…”