Increased formation and persistence of 1,N(6)-ethenoadenine in DNA is not associated with higher susceptibility to carcinogenesis in alkylpurine-DNA-N-glycosylase knockout mice treated with vinyl carbamate.
Ethenobases are promutagenic DNA adducts formed by some environmental carcinogens and products of endogenous lipid peroxidation. Mutation spectra in tumors induced in mice by urethane or its metabolite vinyl carbamate (Vcar) are compatible with 1,N(6)-ethenoadenine (epsilonA) being an initiating lesion in the development of these tumors. As alkylpurine-DNA-N-glycosylase (APNG) releases epsilonA from DNA in vitro, wild-type and APNG-/- C57Bl/6J mice were treated with Vcar and levels of epsilonA and 3,N(4)-ethenocytosine (epsilonC), which is not a substrate of APNG, were analyzed in liver and lung DNA. At 6 h after the last dose, levels of epsilonA were 1.6-fold higher in DNA from APNG-/- mice and subsequently persisted at higher levels for longer than in DNA from wild-type animals, confirming that epsilonA is released by APNG in vivo. In contrast, approximately 14-fold lower levels of epsilonC were induced by Vcar, and the kinetics of formation and persistence of epsilonC was similar in the two mouse strains. The carcinogenicity of Vcar was compared in APNG-/- and wild-type suckling mice given a single dose of Vcar (30 or 150 nmol/g). After 1 year, only mice in the high-dose group developed hepatocellular carcinoma; however, the incidence was not higher in APNG-/- mice. Although higher levels and increased persistence of epsilonA was observed in hepatic DNA from APNG-/- mice at 150 nmol/g Vcar, apoptosis and cell proliferation levels were similar in both strains of mice. This may explain why differences in epsilonA formation/persistence observed here did not result in higher susceptibility of APNG-/- mice to hepatocarcinogenesis.
Barbin
Alain
A
International Agency for Research on Cancer (IARC), Lyon, France.
Wang
Rong
R
O'Connor
Peter J
PJ
Elder
Rhoderick H
RH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000187:drug effects* / Q000378:metabolism*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency* / Q000235:genetics; D004260:DNA Repair / Q000502:physiology*; D003839:Deoxyadenosines / Q000096:biosynthesis / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014520:Urethane / Q000031:analogs & derivatives* / Q000633:toxicity*
D002273:Carcinogens; D003839:Deoxyadenosines; D014520:Urethane; C032221:1,N(6)-ethenodeoxyadenosine; C017963:vinyl carbamate; D004247:DNA; D045647:DNA Glycosylases; C076131:DNA-3-methyladenine glycosidase II