In vitro metabolism and DNA adduct formation from the mutagenic environmental contaminant 2-nitrofluoranthene.
The metabolism and DNA adduct formation by the mutagenic environmental contaminant 2-nitrofluoranthene (2-NFA) were studied. Incubation under aerobic conditions with liver microsomes of rats pretreated with 3-methylcholanthrene yielded trans-7,8-dihydroxy-7,8-dihydro-2-nitrofluoranthene, trans-9,10-dihydroxy-9,10-dihydro-2-nitrofluoranthene, and 7-, 8-, and 9-phenolic metabolites. When the epoxide hydrolase inhibitor 3,3,3-trichloropropylene was present in the incubation, only phenolic metabolites were detected. Under hypoxic conditions, 2-aminofluoranthene was obtained, together with a trace of the ring-oxidized metabolites. The activated metabolite, N-hydroxy-2-aminofluoranthene, was prepared in situ and reacted with calf thymus DNA. Upon enzymatic hydrolysis of the DNA and purification by HPLC, a C8-substituted deoxyguanosine adduct, N-(deoxyguanosin-8-yl)-2-aminofluoranthene, was identified by mass and proton NMR spectral analysis. This adduct was also formed at a level of 10 pmol/mg of DNA when 2-NFA was metabolized by xanthine oxidase, 6 pmol/mg of DNA from incubation with liver microsomes of rats pretreated with 3-methylcholanthrene, and 3-pmol/mg of DNA from metabolism by liver microsomes of rats pretreated with phenobarbital.
Herreno-Saenz
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National Center for Toxicological Research, Jefferson, Arkansas 72079.
Evans
F E
FE
Heinze
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T
Lewtas
J
J
Fu
P P
PP
D000818:Animals; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage; D005449:Fluorenes / Q000378:metabolism* / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D013950:Thymus Gland / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D002274:Carcinogens, Environmental; D005449:Fluorenes; D009153:Mutagens; D004247:DNA; D014969:Xanthine Oxidase; C049030:2-nitrofluoranthene