DNA adduct formation in target tissues of Sprague-Dawley rats, CD-1 mice and A/J mice following tumorigenic doses of 1-nitropyrene.
Recent reports have indicated that 1-nitropyrene is tumorigenic in laboratory animals. Since it is generally accepted that the covalent binding of carcinogens to DNA is causally related to tumorigenesis, we used 32P-postlabeling to examine the DNA adducts present in target tissues. 1-Nitropyrene (99.85-99.98% 1-nitropyrene, 0.15-0.02% 1,3-, 1,6- and 1,8-dinitropyrene by mass spectral analyses) was administered to Sprague-Dawley rats, CD-1 mice and A/J mice according to three tumorigenesis protocols. In DNA obtained from the injection site of Sprague-Dawley rats, two major adducts were observed. Based upon their chromatographic behavior and sensitivities to treatment with nuclease P1 and hydrazine, these adducts were identified as N-(deoxyguanosin-8-yl)-1-aminopyrene (dG-C8-AP) and N-(deoxyguanosin-8-yl)-1-amino-3-, 6- and/or 8-nitropyrene (dG-C8-ANP), which are adducts derived from the nitroreduction of 1-nitropyrene and dinitropyrenes respectively. In mammary gland DNA from Sprague-Dawley rats, two adducts were found. One of these had chromatographic characteristics and hydrazine and nuclease P1 sensitivities similar to dG-C8-AP, while the identity of the other adduct is presently unknown. The only DNA adduct detected in the livers of newborn CD-1 mice and the lungs of A/J mice was dG-C8-ANP. The presence of dG-C8-AP in the injection site and mammary gland of the Sprague-Dawley rats indicates that nitroreduction is involved in the metabolic activation of 1-nitropyrene in these tissues. Since an unidentified adduct was also found in the mammary gland, other pathways are important in this tissue. The presence of only dinitropyrene DNA adducts in the livers of CD-1 mice and lungs of A/J mice indicates that dinitropyrenes are activated very efficiently to electrophilic metabolites, to an extent far better than 1-nitropyrene.
Smith
B A
BA
National Center for Toxicological Research, Jefferson, AR 72079.
Korfmacher
W A
WA
Beland
F A
FA
D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D004247:DNA / Q000378:metabolism*; D005260:Female; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008805:Mice, Inbred A; D008815:Mice, Inbred Strains; D010761:Phosphorus Radioisotopes; D011721:Pyrenes / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014316:Tritium
D010761:Phosphorus Radioisotopes; D011721:Pyrenes; D014316:Tritium; D004247:DNA; C032668:1-nitropyrene