This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kadlubar, F. F. Articles by Geacintov, N. E. Search for Related Content PubMed PubMed Citation Articles by Kadlubar, F. F. Articles by Geacintov, N. E.

Structural Consequences of Modification of the Oxygen Atom of Guanine in DNA by the Carcinogen N-Hydroxy-1-naphthylamine¹

National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas 72079 [F. F. K., W. B. M., T. J. F.]; Centre d'Etudes Nucleaires de Saclay, 91190 Gif sur Yvette, France [A. G. G.]; Institut Universitaire de Technologie, Paris XI, Cachan, France [A. G. G.]; and Chemistry Department, New York University, New York, New York 10003 [H. Y., N. E. G.]

Since the ultimate carcinogen N-hydroxy-1-naphthylamine (N-HO-1-NA) reacts selectively with DNA at the O⁶ atom of the guanine base, an investigation of the consequences of this potentially mispairing lesion upon DNA structure was under-taken. Fluorescence spectroscopic studies, which detected only the major N-HO-1-NA-O⁶-guanine adduct, showed that the fluorescence decay rate for the naphthyl residue in DNA was similar to that for N-HO-1-NA in solution. Furthermore, the naphthyl fluorescence was efficiently quenched by O₂ and was relatively unaffected by Ag⁺, indicating the free accessibility of the bound naphthyl moiety to the surrounding solution. Electric linear dichroism studies revealed that the transition moment of the 1-naphthylamine adducts, which are aligned along the short axis of the naphthyl ring, tended to be parallel (within 20°) to the transition moment of the DNA bases and thus perpendicular to the DNA helical axis. From these data, spacefilling molecular models of DNA containing the major O⁶-substituted guanine-naphthylamine adduct were constructed. A model is shown in which the naphthyl residue resides in the major groove of the DNA with complete freedom of rotation about the naphthyl-1-NH bond without causing major conformational changes in the DNA helical structure.

Quite unexpectedly, N-HO-1-NA decreased the thermal stability of the DNA in proportion to the degree of reaction. However, derivative melting curves suggested that a major part of this effect is due to preferential reaction with high-melting satellite components (guanine:cytosine-rich regions) of the DNA and that the effect on the stability of the main component is considerably less. In contrast, reaction of DNA with N-acetoxy-2-acetylaminofluorene had qualitatively different effects on thermal stability, indicating that binding of the fluorene residues to DNA occurred randomly. The role of N-HO-1-NA-DNA adducts as promutagenic, site-selective lesions leading to the initiation of N-HO-1-NA carcinogenesis is proposed.

¹ Supported in part by NCI PHS Grant CA 20851 and by Department of Energy (EP-78-02-4959 E(11-1)2836).

² To whom requests for reprints should be addressed.

Received 12/ 9/80. Accepted 2/17/81.