In vivo metabolism and genotoxic effects of nitrated polycyclic aromatic hydrocarbons.
During incomplete combustion of organic matter, nitro-polycyclic aromatic hydrocarbons (nitro-PAHs), are formed in a reaction that is catalyzed by a low pH. 2-Nitrofluorene (NF), a marker for nitro-PAHs, is metabolized in vivo by two different routes. After inhalation, potent mutagenic metabolites, hydroxylated nitrofluorenes (OH-NFs), are formed. The metabolites are distributed by systemic circulation. After oral administration, NF is reduced to the corresponding amine, a reaction mediated by the intestinal microflora. This metabolite is acetylated to 2-acetylaminofluorene (AAF), a potent carcinogen. Further ring-hydroxylation of AAF leads to detoxification and excretion. Induction of cytochrome P450s affects the metabolism, and more OH-NFs are formed. As a consequence, more mutagenic metabolites are found in the circulation. OH-NFs are excreted in the bile as, in terms of mutagenicity, totally harmless glucuronide conjugates. When these conjugates are excreted via the bile, intestinal beta-glucuronidase can liberate direct-acting mutagens in the intestine. Thus, inhalation of NF can lead to formation of potent mutagens in the intestine. NF is a direct-acting mutagen in bacterial assays and an initiator and promoter of the carcinogenic process, and gives rise to DNA adduct formation in laboratory animals.
Möller
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Unit for Analytical Toxicology, Karolinska Institute, Huddinge, Sweden.
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D002853:Chromatography, Liquid; D005449:Fluorenes / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D013058:Mass Spectrometry; D009153:Mutagens / Q000633:toxicity*; D009574:Nitro Compounds / Q000378:metabolism* / Q000633:toxicity*; D011083:Polycyclic Compounds / Q000378:metabolism* / Q000633:toxicity*
D005449:Fluorenes; D009153:Mutagens; D009574:Nitro Compounds; D011083:Polycyclic Compounds; C019499:2-nitrofluorene