Carcinogenesis, Vol. 20, No. 12, 2287-2292,
December 1999
© 1999 Oxford University Press
Carcinogenesis |
Comparison of the mutagenic properties of 8-oxo-7,8-dihydro-2'-deoxyadenosine and 8-oxo-7,8-dihydro-2'-deoxyguanosine DNA lesions in mammalian cells
Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA
The comparative mutagenicity of 8-oxo-7,8-dihydro-2'-deoxyadenosine (8-oxodA) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) was explored using simian kidney (COS-7) cells. Oligodeoxynucleotides [5'-TCCTCCT- G1X2CCTCTC or 5'-TCCTCCTX1G2CCTCTC (X = dA, dG, 8-oxodA or 8-oxodG)] containing 8-oxodA or 8-oxodG positioned within codon 60 or 61 of the non-coding strand of human c-Ha-ras1 gene were inserted into a single-stranded phagemid shuttle vector. The vector was replicated in COS-7 cells and the progeny plasmids were used to transform Escherichia coli DH10B. The transformants were analyzed by oligodeoxynucleotide hybridization and DNA sequence analysis to establish the mutation frequency and specificity. When 8-oxodA was positioned at X1, targeted Aoxo
C transversions were detected; the mutation frequency was 1.2%. When 8-oxodA was positioned at X2, one targeted mutant among 416 colonies screened (an AoxoG transition) was detected. Thus, the mutation frequency and spectrum of 8-oxodA depend on the sequence context of the lesion. The mutation frequency of 8-oxodG at X1 and X2 was 5.2 and 6.8%, respectively. GoxoT transversions dominated the spectrum, accompanied by small numbers of GoxoA transitions and GoxoC transversions. We conclude that 8-oxodA has mutagenic potential in mammalian cells, generating AC transversions. However, when tested under similar conditions, the mutation frequency of 8-oxodA is at least four times lower than that of 8-oxodG.
Abbreviations: 8-oxodA, 8-oxo-7,8-dihydro-2'-deoxyadenosine; 8-oxodG, 8-oxo-7,8-dihydro-2'-deoxyguanosine; ds vector, double-stranded vector; HPLC, high-performance liquid chromatography; PAGE, polyacrylamide gel electrophoresis; ss vector, single-stranded vector.
1 To whom correspondence should be addressed Email: shinya{at}pharm.som.sunysb.edu
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