Reaction mechanisms of trans-9,10-dihydroxy-anti-7,8-epoxy-7,8,9,10-tetrahydro-3- methylcholanthrene with DNA in aqueous solutions. Conformation of adducts

M. H. Kim, Nicholas Geacintov, D. G. McQuillen, M. Pope, R. G. Harvey

Research output: Contribution to journalArticle

Abstract

The reaction mechanisms of trans-9,10-dihydroxy-anti-7,8-epoxy-7,8,9,10-tetrahydro-3- methylcholanthrene (anti-3-MCDE) in aqueous phosphate buffer solutions (pH 7, 24°C) containing double-stranded DNA, and the structure of the covalent adduct formed, were studied by utilizing the techniques of absorption, fluorescence and linear dichroism spectroscopy. The results were compared with those obtained with the widely studied trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a] pyrene (BaPDE). The reaction mechanisms are similar in both cases since 3-MCDE also appears to form physical complexes which give rise to an acceleration of the rate of reaction of the diol-epoxide (by as much as a factor of 30 at pH 7, depending on the DNA and salt concentrations). While in the case of 3-MCDE the physical association constant is about four times lower, and the overall rate of reaction is at least five times smaller (depending on the DNA concentration) than in the case of BaPDE, the level of covalent binding is two times higher (18 ± 2% of the 3-MCDE molecules appear as covalent adducts, the remainder forming hydrolysis products). In a novel extension of flow linear dichroism techniques, it is shown that the orientations of small aromatic moieties bound to DNA whose absorption spectra overlap with those of the nucleic acid residues below 300 nm can be studied; the dichroism at 265 nm resulting from the anthracene-like aromatic residue of 3-MCDE covalently bound to DNA suggests that its long axis tends, on average, to be tilted away from the average orientations of the planes of the nucleic acids. This conformation is similar to the one observed with adducts derived from the covalent binding of the highly tumorigenic (+) enantiomer of BaPDE, while the adducts derived from other biologically less active stereoisomers of BaPDE are characterised by conformations in which the aromatic moieties tend to be more parallel to the planes of the nucleic acid bases. Differences in the bioligical acitvities of the various polycyclic aromatic diol-epoxides are discussed in terms of these conformations and the abilities of these molecules to bind convalently to DNA.

Original languageEnglish (US)
Pages (from-to)41-47
Number of pages7
JournalCarcinogenesis
Volume7
Issue number1
StatePublished - 1986

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Reaction Mechanism
Epoxy
Conformation
Conformations
DNA
Nucleic acids
Dichroism
Molecules
Tend
Nucleic Acids
Epoxy Compounds
Absorption Spectra
Remainder
Phosphate
Salt
Fluorescence
Buffer
Spectroscopy
Overlap
Absorption

ASJC Scopus subject areas

  • Cancer Research
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Physiology
  • Behavioral Neuroscience

Cite this

Reaction mechanisms of trans-9,10-dihydroxy-anti-7,8-epoxy-7,8,9,10-tetrahydro-3- methylcholanthrene with DNA in aqueous solutions. Conformation of adducts. / Kim, M. H.; Geacintov, Nicholas; McQuillen, D. G.; Pope, M.; Harvey, R. G.

In: Carcinogenesis, Vol. 7, No. 1, 1986, p. 41-47.

Research output: Contribution to journalArticle

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abstract = "The reaction mechanisms of trans-9,10-dihydroxy-anti-7,8-epoxy-7,8,9,10-tetrahydro-3- methylcholanthrene (anti-3-MCDE) in aqueous phosphate buffer solutions (pH 7, 24°C) containing double-stranded DNA, and the structure of the covalent adduct formed, were studied by utilizing the techniques of absorption, fluorescence and linear dichroism spectroscopy. The results were compared with those obtained with the widely studied trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a] pyrene (BaPDE). The reaction mechanisms are similar in both cases since 3-MCDE also appears to form physical complexes which give rise to an acceleration of the rate of reaction of the diol-epoxide (by as much as a factor of 30 at pH 7, depending on the DNA and salt concentrations). While in the case of 3-MCDE the physical association constant is about four times lower, and the overall rate of reaction is at least five times smaller (depending on the DNA concentration) than in the case of BaPDE, the level of covalent binding is two times higher (18 ± 2{\%} of the 3-MCDE molecules appear as covalent adducts, the remainder forming hydrolysis products). In a novel extension of flow linear dichroism techniques, it is shown that the orientations of small aromatic moieties bound to DNA whose absorption spectra overlap with those of the nucleic acid residues below 300 nm can be studied; the dichroism at 265 nm resulting from the anthracene-like aromatic residue of 3-MCDE covalently bound to DNA suggests that its long axis tends, on average, to be tilted away from the average orientations of the planes of the nucleic acids. This conformation is similar to the one observed with adducts derived from the covalent binding of the highly tumorigenic (+) enantiomer of BaPDE, while the adducts derived from other biologically less active stereoisomers of BaPDE are characterised by conformations in which the aromatic moieties tend to be more parallel to the planes of the nucleic acid bases. Differences in the bioligical acitvities of the various polycyclic aromatic diol-epoxides are discussed in terms of these conformations and the abilities of these molecules to bind convalently to DNA.",
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AU - Geacintov, Nicholas

AU - McQuillen, D. G.

AU - Pope, M.

AU - Harvey, R. G.

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