DNA adduct formation in liver following the administration of [3H]2-nitrofluorene to rats in vivo.
The formation of RNA and DNA adducts by the environmental pollutant 2-nitrofluorene (2-NF) has been investigated in rat liver in vivo. The adduct pattern was studied after trifluoroacetic acid hydrolysis of DNA or RNA, followed by analysis of the adducts by HPLC. This was also done by enzymatic hydrolysis of DNA, followed by 32P-postlabeling. Both after oral and i.v. administration of [3H]2-NF, one major adduct was found. This adduct did not co-migrate with one of the known adducts of 2-(acetyl)-aminofluorene, N-deoxyguanosin-8-yl-2-aminofluorene (dG-C8-AF), which could have been formed after nitroreduction of 2-NF. 32P-Postlabeling revealed that two minor adducts were also formed, one of which was dG-C8-AF. The observation that the major adduct was also formed after i.v. administration of 2-NF to bile duct-catheterized rats makes a role for the intestinal microflora in the formation of this adduct very unlikely. In vitro experiments with inhibitors of the enzyme epoxide hydrolase indicated that epoxidation of 2-NF may play a role in the microsomal bioactivation of this compound.
Wierckx
F C
FC
Division of Toxicology, Center for Bio-Pharmaceutical Sciences, University of Leiden, The Netherlands.
Wedzinga
R
R
Timmers-Reker
A J
AJ
Beland
F A
FA
Meerman
J H
JH
Mulder
G J
GJ
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000502:physiology; D004852:Epoxy Compounds / Q000494:pharmacology; D005449:Fluorenes / Q000378:metabolism*; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D012313:RNA / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014239:Trichloroepoxypropane / Q000494:pharmacology; D014269:Trifluoroacetic Acid / Q000494:pharmacology
D002273:Carcinogens; D004852:Epoxy Compounds; D005449:Fluorenes; C019499:2-nitrofluorene; C031838:N-(deoxyguanosin-8-yl)-2-aminofluorene; D014239:Trichloroepoxypropane; C018776:N-(deoxyguanosin-8-yl)acetylaminofluorene; D012313:RNA; D009637:Masoprocol; D004247:DNA; D015073:2-Acetylaminofluorene; C013690:styrene oxide; D014269:Trifluoroacetic Acid; D004851:Epoxide Hydrolases; D003849:Deoxyguanosine