Carcinogenesis, Vol. 20, No. 2, 261-268,
February 1999
© 1999 Oxford University Press
The major, N2-dG adduct of (+)-anti-B[a]PDE induces G
A mutations in a 5'-AGA-3' sequence context
Department of Biology, Boston University, 2 Cummington Street, Boston, MA 02215 and
1 Department of Chemistry, New York University, New York, NY 10003, USA
Previously, in a random mutagenesis study, the (+)-anti diol epoxide of benzo[a]pyrene [(+)-anti-B[a]PDE] was shown to induce a complex mutational spectrum in the supF gene of an Escherichia coli plasmid, which included insertions, deletions and base substitution mutations, notably a significant fraction of GC
TA, GCAT and GCCG mutations. At some sites, a single type of mutation dominated and to understand individual mutagenic pathways these sites were chosen for study by site-specific means to determine whether the major adduct, [+ta]-B[a]P–N2-dG, was responsible. [+ta]-B[a]P–N2-dG was shown to induce ~95% GT mutations in a 5'-TGC-3' sequence context and ~80% GA mutations in a 5'-CGT-3' sequence context. (+)-anti-B[a]PDE induced principally GCCG mutations in the G133 sequence context (5'-AGA-3') in studies using both SOS-uninduced or SOS-induced E.coli. Herein, [+ta]-B[a]P–N2-dG is shown to induce principally GA mutations (>90%) either without or with SOS induction in a closely related 5'-AGA-3' sequence context (identical over 7 bp). This is the first time that there has been a discrepancy between the mutagenic specificity of (+)-anti-B[a]PDE versus [+ta]-B[a]P–N2-dG. Eight explanations for this discordance are considered. Four are ruled out; e.g. the second most prevalent adduct [+ca]-B[a]P–N2-dG also induces a preponderance of GA mutations (>90%), so it also is not responsible for (+)-anti-B[a]PDE-induced G133C mutations. The four explanations not ruled out are discussed and include that another minor adduct might be responsible and that the 5'-AGA-3' sequence context differed slightly in the studies with [+ta]-B[a]P–N2-dG versus (+)-anti-B[a]PDE. In spite of the discordance, [+ta]-B[a]P–N2-dG induces GA mutations in the context studied herein and this result has proven useful in generating a hypothesis for what conformations of [+ta]-B[a]P–N2-dG are responsible for GT versus GA mutations.
Abbreviations: (+)-anti-B[a]PDE, 7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; B[a]P, benzo[a]pyrene; GHD, gapped heteroduplex; MF, mutation frequency; O-G, 5'-TTTAG133AG131ACC-3'; PAH, polycyclic aromatic hydrocarbon.
2 To whom correspondence should be addressed Email: loechler{at}bio.bu.edu
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