Initial levels of azoxymethane-induced DNA methyl adducts are not predictive of tumor susceptibility in inbred mice

Toxicology and Applied Pharmacology
A PapanikolaouD W Rosenberg

Abstract

Inbred mice vary in susceptibility to colon carcinogens such as 1,2-dimethylhydrazine (DMH). Differential susceptibility may depend, in part, on formation of promutagenic DNA methyl adducts within target colonic mucosa. The present study was undertaken to evaluate the extent of DNA adduct formation in susceptible (SWR) and resistant (AKR) mice acutely exposed to the colon carcinogen azoxymethane (AOM), a direct metabolite of DMH. In the first experiment, 8-week-old SWR and AKR mice were treated i.p. with 20 mg/kg AOM and sacrificed 6 h later. DNA was isolated from distal colon and liver, and O6-methylguanine (O6-MeGua) adduct levels were assessed by immunoslot blot (ISB) analysis, using a monospecific antibody raised against O6-methyldeoxyguanosine. HPLC-fluorescence detection was also used to quantitate 06-MeGua and 7-methylguanine (7-MeGua), and to generate standard curves. At 6 h, both O6-MeGua and 7-MeGua were significantly higher (2- to 3-fold, p < 0.05) in AKR colon, while an opposite pattern was found in liver. In Experiment 2, mice were injected with AOM (20 mg/kg) and euthanized 12 and 48 h later. At 12 h, O6-MeGua levels were higher in colons (1.4-fold) of SWR mice. Forty-eight hours after treatment, however, adduct l...Continue Reading

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Citations

Apr 7, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ilenia D'ErricoAntonio Moschetta
May 23, 2013·Proceedings of the National Academy of Sciences of the United States of America·Bo HuRichard A Flavell
Nov 28, 2008·Carcinogenesis·Daniel W RosenbergTakuji Tanaka
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Apr 10, 2014·Stem Cells·Masanao NasunoYasuhisa Shinomura
May 11, 1999·Experimental and Molecular Pathology·D A DelkerD W Rosenberg
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Oct 8, 2014·Proceedings of the National Academy of Sciences of the United States of America·Elena BellafanteAntonio Moschetta
Jul 20, 2011·Experimental Biology and Medicine·Khalid S Al-NumairMohamed A Alsaif
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