Structural consequences of modification of the oxygen atom of guanine in DNA by the carcinogen N-hydroxy-1-naphthylamine

F. F. Kadlubar, W. B. Melchior, T. J. Flammang, A. G. Gagliano, H. Yoshida, N. E. Geacintov

Research output: Contribution to journalArticle

Abstract

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 undertaken. 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, space-filling 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.

Original languageEnglish (US)
Pages (from-to)2168-2174
Number of pages7
JournalCancer Research
Volume41
Issue number6
StatePublished - 1981

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Guanine
Carcinogens
Oxygen
DNA
Fluorescence
Freezing
N-hydroxy-1-naphthylamine
Acetoxyacetylaminofluorene
Hot Temperature
1-Naphthylamine
Molecular Models
DNA Adducts
Cytosine
Carcinogenesis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kadlubar, F. F., Melchior, W. B., Flammang, T. J., Gagliano, A. G., Yoshida, H., & Geacintov, N. E. (1981). Structural consequences of modification of the oxygen atom of guanine in DNA by the carcinogen N-hydroxy-1-naphthylamine. Cancer Research, 41(6), 2168-2174.

Structural consequences of modification of the oxygen atom of guanine in DNA by the carcinogen N-hydroxy-1-naphthylamine. / Kadlubar, F. F.; Melchior, W. B.; Flammang, T. J.; Gagliano, A. G.; Yoshida, H.; Geacintov, N. E.

In: Cancer Research, Vol. 41, No. 6, 1981, p. 2168-2174.

Research output: Contribution to journalArticle

Kadlubar, FF, Melchior, WB, Flammang, TJ, Gagliano, AG, Yoshida, H & Geacintov, NE 1981, 'Structural consequences of modification of the oxygen atom of guanine in DNA by the carcinogen N-hydroxy-1-naphthylamine', Cancer Research, vol. 41, no. 6, pp. 2168-2174.
Kadlubar, F. F. ; Melchior, W. B. ; Flammang, T. J. ; Gagliano, A. G. ; Yoshida, H. ; Geacintov, N. E. / Structural consequences of modification of the oxygen atom of guanine in DNA by the carcinogen N-hydroxy-1-naphthylamine. In: Cancer Research. 1981 ; Vol. 41, No. 6. pp. 2168-2174.
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abstract = "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 undertaken. 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, space-filling 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.",
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AU - Kadlubar, F. F.

AU - Melchior, W. B.

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AU - Gagliano, A. G.

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AU - Geacintov, N. E.

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N2 - 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 undertaken. 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, space-filling 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.

AB - 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 undertaken. 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, space-filling 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.

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