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.
AffiliationInternational Agency for Research on Cancer (IARC), Lyon, France.
MetadataShow full item record
AbstractEthenobases 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.
CitationIncreased 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. 2003, 63 (22):7699-703 Cancer Res.
- Alkylpurine-DNA-N-glycosylase excision of 7-(hydroxymethyl)-1,N6-ethenoadenine, a glycidaldehyde-derived DNA adduct.
- Authors: Wang P, Guliaev AB, Elder RH, Hang B
- Issue date: 2006 Jan 5
- Endogenous deoxyribonucleic Acid (DNA) damage in human tissues: a comparison of ethenobases with aldehydic DNA lesions.
- Authors: Barbin A, Ohgaki H, Nakamura J, Kurrer M, Kleihues P, Swenberg JA
- Issue date: 2003 Nov
- Decreased repair activities of 1,N(6)-ethenoadenine and 3,N(4)-ethenocytosine in lung adenocarcinoma patients.
- Authors: Speina E, Zielińska M, Barbin A, Gackowski D, Kowalewski J, Graziewicz MA, Siedlecki JA, Oliński R, Tudek B
- Issue date: 2003 Aug 1
- Effect of ethanol on the tumorigenicity of urethane (ethyl carbamate) in B6C3F1 mice.
- Authors: Beland FA, Benson RW, Mellick PW, Kovatch RM, Roberts DW, Fang JL, Doerge DR
- Issue date: 2005 Jan
- Targeted deletion of alkylpurine-DNA-N-glycosylase in mice eliminates repair of 1,N6-ethenoadenine and hypoxanthine but not of 3,N4-ethenocytosine or 8-oxoguanine.
- Authors: Hang B, Singer B, Margison GP, Elder RH
- Issue date: 1997 Nov 25