Metabolic activation of 1-nitropyrene to a mammalian cell mutagen and a carcinogen.
1. The mutagenicity of 1-nitropyrene metabolites in Chinese hamster ovary (CHO) cells, in the absence of rat liver S9, decreased in the order 6-hydroxy-1-nitropyrene > 1-nitropyrene 9,10-oxide > 1-nitropyrene 4,5-oxide approximately 3-hydroxy-1-nitropyrene approximately 8-hydroxy-1-nitropyrene > 1-nitropyrene. The order of mutagenicity with rat liver S9 was 1-nitropyrene 4,5-oxide approximately 6-hydroxy-1-nitropyrene approximately 1-nitropyrene 9,10-oxide > 3-hydroxy-1-nitropyrene approximately 1-nitropyrene > 8-hydroxy-1-nitropyrene. 2. 1-Nitropyrene 4,5-oxide reacted with calf thymus DNA to give one or several closely related adducts. The same adducts were detected in CHO cells incubated with 1-nitropyrene 4,5-oxide. Inclusion of a nitroreductase, xanthine oxidase, in the incubations with calf thymus DNA resulted in the formation of an additional adduct identified as N-(deoxyguanosin-8-yl)-1-aminopyrene (dG-C8-AP). 3. 1-Nitropyrene 9,10-oxide reacted with calf thymus DNA to give an adduct pattern similar to that observed with 1-nitropyrene 4,5-oxide. Incubation of 1-nitropyrene 9,10-oxide with CHO cells resulted in the formation of the same adducts along with dG-C8-AP. 4. dG-C8-AP and N-(deoxyguanosin-8-yl)-1-amino-x-nitropyrene (x = 3, 6 or 8; dG-C8-ANP) were detected in injection site DNA from Sprague-Dawley rats treated with 1-nitropyrene. In mammary gland DNA, dG-C8-AP and an unidentified adduct were found. dG-C8-ANP was the only DNA adduct detected in the livers of newborn CD-1 mice and the lungs of A/J mice dosed with 1-nitropyrene.
Beland
F A
FA
National Center for Toxicological Research, Jefferson, AR 72079.
Smith
B A
BA
Thornton-Manning
J R
JR
Heflich
R H
RH
D000818:Animals; D001711:Biotransformation; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics* / Q000633:toxicity; D011721:Pyrenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014020:Tissue Extracts / Q000494:pharmacology
D002273:Carcinogens; D009153:Mutagens; D011721:Pyrenes; D014020:Tissue Extracts; C057066:1-nitropyrene-4,5-oxide; C057067:1-nitropyrene-9,10-oxide; D004247:DNA; C032668:1-nitropyrene