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Mutagenesis by O(6)-[4-oxo-4-(3-pyridyl)butyl]guanine in Escherichia coli and human cells.
- Source :
-
Chemical research in toxicology [Chem Res Toxicol] 2002 Feb; Vol. 15 (2), pp. 165-9. - Publication Year :
- 2002
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Abstract
- Site-specific mutagenesis by O(6)-[4-oxo-4-(3-pyridyl)butyl]guanine (O(6)-pobGua), a product of DNA pyridyloxobutylation by metabolites of the tobacco-specific nitrosamines N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), was studied in Escherichia coli strain DH10B and human kidney cells (293) when the modified base was incorporated in either a double-stranded or a gapped shuttle vector. In the repair-competent E. coli strain, less than 3% of the colonies produced by double-stranded vectors harboring the modified base were mutant whereas 96% were mutant when DH10B cells were transformed with modified gapped vectors. By contrast, transformation of DH10B cells with plasmids derived from O(6)-pobGua-containing double-stranded and gapped vectors previously replicated in 293 cells produced 7 and 16% mutant colonies, respectively. These percentages increased to 42 and 82%, respectively, when the 293 cells were pretreated with O(6)-benzylguanine to inactivate the O(6)-alkylguanine-DNA alkyltransferase protein. These findings confirm that the adduct is readily repaired by the human O(6)-alkylguanine-DNA alkyltransferase in both double-stranded and gapped vectors and suggest that it is also highly mutagenic in both human cells and E. coli. In the E. coli strain, the adduct produced exclusively G --> A transition mutations although in human 293 cells it also produced G --> T transversions and more complex mutations in addition to G --> A transitions. These data suggest that O(6)-[4-oxo-4-(3-pyridyl)butyl]guanine can contribute significantly to the mutagenic risk posed by exposure to both NNN and NNK in tobacco smoke.
- Subjects :
- Cell Line
DNA Adducts metabolism
DNA Repair drug effects
Escherichia coli genetics
Guanine metabolism
Kidney cytology
Kidney embryology
Kidney metabolism
Mutagenesis, Site-Directed drug effects
Mutagens metabolism
DNA Adducts toxicity
Escherichia coli drug effects
Guanine analogs & derivatives
Guanine toxicity
Mutagens toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 0893-228X
- Volume :
- 15
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Chemical research in toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 11849042
- Full Text :
- https://doi.org/10.1021/tx0101245