Dependence of conformations of benzo[a]pyrene diol epoxide-DNA adducts derived from stereoisomers of different tumorigenicities on base sequence

Camille J. Roche, Alan M. Jeffrey, Bing Mao, Anna Alfano, Seog K. Kim, Victor Ibanez, Nicholas Geacintov

Research output: Contribution to journalArticle

Abstract

The conformations of covalent adducts derived from the binding of the highly tumorigenic stereoisomer (+)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE] and its nontumorigenic (-)-anti-BPDE isomer with poly[(dG)·(dC)], poly[(dG-dC)·(dG-dC)], poly[(dT-dC)·(dG-dA)], and poly[(dA-dC)·(dG-dT)] were investigated by employing UV absorbance and linear dichroism methods. The degrees of orientation of the BPDE residues (bound covalently to N2 of deoxyguanosine), relative to the DNA bases, are most pronounced in the alternating and nonalternating (dG)·(dC) polymers and decrease in polymers with neighboring dA·dT base pairs. The tumorigenic (+)-anti-BPDE isomer gives rise predominantly to external (solvent-exposed) site II adducts, while the (-)-enantiomer gives rise predominantly to site I adducts with significant carcinogen-nucleoside interactions. In the mixed (dA-dC)·(dG-dT) and (dT-dC)·(dG-dA) copolymers, the (+)-anti-BPDE isomer also binds predominantly to N2 of deoxyguanosine, but the adducts are weakly oriented with respect to the DNA bases. The incidence of site II adducts is considerably reduced as compared to the (dG)·(dC) and (dG-dC)·(dG-dC) polymers, and there is a greater proportion of site I adducts; the presence of a significant proportion of unordered adduct forms is also suggested from the diffuseness and broadness of the absorption spectra in the dA·dT base pair containing polymers. The preference of formation of site II adducts in dG-rich sequences in the case of the biologically highly active (+)-anti-BPDE isomer is discussed in terms of the known binding and mutation spectra.

Original languageEnglish (US)
Pages (from-to)311-317
Number of pages7
JournalChemical Research in Toxicology
Volume4
Issue number3
StatePublished - 1991

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7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Stereoisomerism
DNA Adducts
Benzo(a)pyrene
Epoxy Compounds
Conformations
Isomers
Polymers
Deoxyguanosine
Base Pairing
Poly T
Enantiomers
DNA
Dichroism
Nucleosides
Carcinogens
Absorption spectra
Copolymers
Mutation
Incidence

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Dependence of conformations of benzo[a]pyrene diol epoxide-DNA adducts derived from stereoisomers of different tumorigenicities on base sequence. / Roche, Camille J.; Jeffrey, Alan M.; Mao, Bing; Alfano, Anna; Kim, Seog K.; Ibanez, Victor; Geacintov, Nicholas.

In: Chemical Research in Toxicology, Vol. 4, No. 3, 1991, p. 311-317.

Research output: Contribution to journalArticle

Roche, Camille J. ; Jeffrey, Alan M. ; Mao, Bing ; Alfano, Anna ; Kim, Seog K. ; Ibanez, Victor ; Geacintov, Nicholas. / Dependence of conformations of benzo[a]pyrene diol epoxide-DNA adducts derived from stereoisomers of different tumorigenicities on base sequence. In: Chemical Research in Toxicology. 1991 ; Vol. 4, No. 3. pp. 311-317.
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