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Volume 272, Number 52, Issue of December 26, 1997 pp. 33211-33219

Lack of Correlation between in Vitro and in Vivo Replication of Precisely Defined Benz[a]anthracene Adducted DNAs

(Received for publication, August 19, 1997, and in revised form, September 3, 1997)

Andrew G. McNees , Mike O'Donnell ^§ , Pamela H. Horton ^¶ , Hye Y. Kim ^¶ , Seong J. Kim ^¶ , Constance M. Harris ^¶ , Thomas M. Harris ^¶ and R. Stephen Lloyd

From the  Department of Human Biological Chemistry and Genetics and Sealy Center for Molecular Science, The University of Texas Medical Branch, Galveston, Texas 77555, the ^§ Microbiology Department, Hearst Research Foundation, and Howard Hughes Medical Institute, Cornell University Medical College, New York, New York 10021, the ^¶ Departments of Chemistry and Biochemistry and the  Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37235

Like other polycyclic aromatic hydrocarbons, certain metabolites of benz[a]anthracene have been implicated as potent carcinogens. These effects are thought to be caused by the covalent binding of these species to nucleophilic groups on the bases of DNA. To address the molecular mechanisms by which these molecules induce mutations, this study employed oligonucleotides containing four site-specific N⁶ adenine-benz[a]anthracene diol epoxide adducts. Using a prokaryotic in vivo replication system, we have shown that both non-bay region anti-trans-benz[a]anthracene adducts are essentially nonmutagenic. In contrast, the bay region anti-trans-benz[a]anthracene lesions do induce point mutations at the adduct site. The mutagenic frequency of these bay region lesions is dependent on the stereochemistry about the adduct-forming bond, as well as the strain of Escherichia coli in which they are replicated. The ability of the bacterial replication machinery to bypass the lesions does not correlate with the differences observed in their mutagenesis. While both non-bay region adducts are readily bypassed in vivo, the bay region adducts are both blocking to approximately the same degree. In vitro studies of the interactions of E. coli DNA polymerase III with these adducts have also been undertaken to further dissect the relationship between adduct structure and biological activity.

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