Chemical carcinogenesis in the nervous system. Preferential accumulation of O6-methylguanine in rat brain deoxyribonucleic acid during repetitive administration of N-methyl-N-nitrosourea
- 1 June 1975
- journal article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 148 (3) , 521-525
- https://doi.org/10.1042/bj1480521
Abstract
The alkylation of purine bases in DNA of several rat tissues was determined during weekly injections (10 mg/kg) of N-[3H]methyl-N-nitrosourea, a dose schedule known to selectively induce tumours of the nervous system. Each group of animals was killed 1 week after the final injection, and the DNA hydrolysates were analysed by chromatography on Sephadex G-10. After five weekly applications, O6-methylguanine had accumulated in brain DNA to an extent which greatly exceeded that in kidney, spleen and intestine. In the liver, the final O6-methylguanine concentration was less than 1% of that in brain. Between the first and the fifth injection, the O6-methylguanine/7-methylguanine ratio in cerebral DNA increased from 0.28 to 0.68. In addition, 3-methylguanine was found to accumulate in brain DNA whereas in the other organs no significant quantities of this base were detectable. The results are compatible with the hypothesis that O6-alkylation of guanine in DNA plays a major role in the induction of tumours by N-methyl-N-nitrosourea and related carcinogens. The kinetics of the increase of O6-methylguanine in cerebral DNA suggest that there is no major cell fraction in the brain which is capable of excising chemically methylated bases from DNA. This repair deficiency could be a determining factor in the selective induction of nervous-system tumours by N-methyl-N-nitrosourea and other neuro-oncogenic compounds.Keywords
This publication has 21 references indexed in Scilit:
- Some chemical aspects of dose-response relationships in alkylation mutagenesisMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 1974
- The Enzymatic Release of O 6 -methylguanine and 3-methyladenine from DNA Reacted with the Carcinogen N -methyl- N -nitrosoureaProceedings of the National Academy of Sciences, 1974
- Methylation of DNA by 3H-14C-methyl-labelled N-methyl-N-nitrosourea—Evidence for transfer of the intact methyl groupChemico-Biological Interactions, 1973
- The properties of
methylguanine in templates for RNA polymeraseBiochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis, 1973 - ALKYLATION OF RAT BRAIN NUCLEIC ACIDS BY N‐METHYL‐N‐NITROSOUREA AND METHYL METHANESULPHONATEJournal of Neurochemistry, 1973
- Methylation of ribonucleic acid by the carcinogens dimethyl sulphate, N-methyl-N-nitrosourea and N-methyl-N′-nitro-N-nitrosoguanidine. Comparisons of chemical analyses at the nucleoside and base levelsBiochemical Journal, 1972
- Nitrosamine-induced carcinogenesis. The alkylation of N-7 of guanine of nucleic acids of the rat by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonateBiochemical Journal, 1971
- Methylation of deoxyribonucleic acid in cultured mammalian cells by N-methyl-N′-nitro-N-nitrosoguanidine. The influence of cellular thiol concentrations on the extent of methylation and the 6-oxygen atom of guanine as a site of methylationBiochemical Journal, 1970
- Possible Relevance of O–6 Alkylation of Deoxyguanosine to the Mutagenicity and Carcinogenicity of Nitrosamines and NitrosamidesNature, 1969
- [Organotropic carcinogenic effects of 65 various N-nitroso- compounds on BD rats].1967