The role of the intestinal microflora in the metabolic activation of nitroarenes and arylamines was studied in female Wistar rats that received a dose of 1 mmol/kg 2-aminofluorene (2-AF) in sunflower oil by gavage. Another group received the same dose of 2-nitrofluorene (2-NF). A third group of animals was used as controls. Germfree (GF) rats, GF rats with a rat microflora (RM) and GF rats with a human microflora (HM) were treated. After treatment with 2-AF significant differences were observed in the formation of haemoglobin (Hb) adducts and DNA adducts. The 2-AF-Hb adduct level (mean +/- SD) observed in GF rats (0.57 +/- 0.13 mumol/g Hb) was considerably lower than that observed in RM rats (5.1 +/- 0.6) and in HM rats (6.2 +/- 1.3). DNA adduct levels showed the opposite pattern: levels of adducts co-migrating with deoxyguanosin-8-yl-aminofluorene (dG-C8-AF) in liver tissue were higher in GF rats (4.6 +/- 1.4 fmol/micrograms DNA) as compared to RM rats (2.6 +/- 0.04) or HM rats (2.0 +/- 0.7). In lung tissue and white blood cells a similar influence of the intestinal microflora on DNA adduct levels was observed. These results suggest that the intestinal microflora cleaves conjugates of 2-AF or N-hydroxy-2-AF, thus facilitating enterohepatic recirculation of these compounds and enhancing the formation of reactive intermediates binding to Hb. The latter is not observed for DNA adduct formation, indicating that most of these adducts have been formed after a single passage through the liver. After treatment with 2-NF, Hb and DNA adduct levels were much lower. An adduct spot was observed that was not present in rats that received 2-AF. In GF animals only very low levels of DNA adducts co-migrating with dG-C8-AF or deoxyguanosin-8-yl-acetyl-aminofluorene and no Hb adducts were observed, indicating that the metabolic activity of the microflora is an essential step in both Hb and DNA adduct formation.
In the covalent binding of nitroarenes to macromolecules, nitroreduction is an important step. The intestinal microflora represents an enormous potential of bacterial nitroreductase activity. As a consequence, the in vivo nitroreduction of orally administered nitroarenes is primarily located in the intestine. In this study, we have investigated the nitroreduction of 2-nitrofluorene (2-NF) by a human microflora in female Wistar rats. Germ-free (GF) rats were equipped with a bacterial flora derived from human feces. Nontreated GF rats and GF animals equipped with a conventional rat flora were used as controls. The composition of the human and the conventional microflora isolated from the rats were consistent with the microflora of the administered feces. In the rats receiving only sunflower seed oil, no adducts were detected. The animals equipped with a human or rat microflora that received 2-aminofluorene (2-AF) formed 2-AF hemoglobin (Hb)-adducts at average levels (mean +/- SEM) of 5.3 +/- 0.3 and 6.7 +/- 0.7 mumole/g Hb, respectively. After 2-NF administration, the adduct levels were 0.022 +/- 0.003 and 0.043 +/- 0.010 mumole/g Hb, respectively. In the GF rats, an adduct level of 0.57 +/- 0.09 was determined after 2-AF administration and no adducts were detected after 2-NF administration. The results show that nitroreduction by an acquired human intestinal microflora and subsequent adduct formation can be studied in the rat in vivo.
In the covalent binding of nitroarenes to macromolecules, nitroreduction is an important step. The intestinal microflora represents an enormous potential of bacterial nitroreductase activity. As a consequence, the in vivo nitroreduction of orally administered nitroarenes is primarily located in the intestine. In this study, we have investigated the nitroreduction of 2-nitrofluorene (2-NF) by a human microflora in female Wistar rats. Germ-free (GF) rats were equipped with a bacterial flora derived from human feces. Nontreated GF rats and GF animals equipped with a conventional rat flora were used as controls. The composition of the human and the conventional microflora isolated from the rats were consistent with the microflora of the administered feces. In the rats receiving only sunflower seed oil, no adducts were detected. The animals equipped with a human or rat microflora that received 2-aminofluorene (2-AF) formed 2-AF hemoglobin (Hb)-adducts at average levels (mean ± SEM) of 5.3 ± 0.3 and 6.7 ± 0.7 pmole/g Hb, respectively. After 2-NF administration, the adduct levels were 0.022 ± 0.003 and 0.043 ± 0.010 pmole/g Hb, respectively. In the GF rats, an adduct level of 0.57 ± 0.09 was determined after 2-AF administration and no adducts were detected after 2-NF administration. The results show that nitroreduction by an acquired human intestinal microflora and subsequent adduct formation can be studied in the rat in vivo.
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