Reactions of stereoisomeric and structurally related bay region diol epoxide derivatives of benz[a]anthracene with DNA. Conformations of non-covalent complexes and covalent carcinogen-DNA adducts

Carberry, Susan E.; Shahbaz, M.; Geacintov, Nicholas E.; Harvey, Ronald G.

doi:10.1016/0009-2797(88)90046-4

Cited by 10 publications

(7 citation statements)

References 37 publications

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“…anti-BPDE undergoes a rapid initial intercalation into the DNA helix as shown by a bathochromic shift in its absorption maximum (6). Similar observations have been made with benz[a]anthracene-3,4-diol 1,2-oxides (26). No such observation was made with 7MBACDEs, which give rise to a small (2-nm) bathochromic shift in their spectra after complexing with DNA (data not shown).…”

Section: Discussionsupporting

confidence: 79%

“…The relatively high level of binding puts 7MBACDE in the same category as aní¿-3-methylcholanthrenediol epoxide, which binds to DNA at twice the levels of anti-BPDE without the intercalative step (alkyl groups are thought to hinder insertion between base pairs of DNA) (6). onti-Benz[a]anthracene-3,4-diol 1,2-oxide also binds covalently to a similar extent (26). The physical association equilibrium constant and the reaction rate constants are lower in the case of 3-MCDE (6).…”

Section: Discussionmentioning

confidence: 95%

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Solvolysis of the bay region diol epoxides of 7-methylbenz[c]acridine in aqueous solution and effect of DNA

Fraser

Duke²,

Holder³

et al. 1990

Chem. Res. Toxicol.

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The hydrolysis of the bay-region syn- and anti-diol epoxides of 7-methylbenz[c]acridine (7MBAC) has been studied in aqueous solution. The rates of reaction have been measured at low ionic strength in the absence and presence of DNA, as a function of pH and temperature, by spectrophotometry and high-pressure liquid chromatography. The major products are the corresponding tetrols, but the syn diastereomer also undergoes rearrangement to a keto diol. The hydrolysis reaction is catalyzed by both acid and DNA and conforms to a mechanism in which a physical association complex is formed between diol epoxide and DNA, followed by two parallel pathways in which the diol epoxide either is hydrolyzed or becomes covalently bound to the DNA. The rate constants are significantly lower than the corresponding ones for the diol epoxides of benzo[a]pyrene. However, the extent of covalent binding of 7MBAC diol epoxides to DNA was found to be 12-30%, depending on the pH of reaction, values that are 2-3 times greater than for the benzo[a]pyrene diol epoxides reacted under the same conditions of low ionic strength. The very small changes (2 nm) in spectroscopic characteristics observed for the covalently bound adduct as compared to the free tetrol suggest that the binding occurs with little intercalation of the compound between the base pairs of DNA.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 95%

Solvolysis of the bay region diol epoxides of 7-methylbenz[c]acridine in aqueous solution and effect of DNA

Fraser

Duke²,

Holder³

et al. 1990

Chem. Res. Toxicol.

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“…Both enantiomers of BPDE cause the unwinding of supercoiled DNA by noncovalent complex formation. Most [16,23,[48][49][50] though not all [49] non-covalent PAH diol epoxide-and other PAH metabolite-DNA [51] complexes appear to be intercalative in nature. Meehan et al [16] have shown that the unwinding angle associated with (±4i)-BPDE intercalation is only 130, about one half of the value observed with EB [37,52].…”

Section: Discussionmentioning

confidence: 99%

Differences in unwinding of supercoiled DNA induced by the two enantiomers ofanti-benzo[a]pyrene diol epoxide

Xu¹,

Birke²,

Carberry³

et al. 1992

Nucl Acids Res

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The unwinding of supercoiled phi X174 RFI DNA induced by the tumorigenic (+) and non-tumorigenic (-) enantiomers of trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) has been investigated by agarose slab-gel and ethidium titration tube gel electrophoresis. The differences in adduct conformations were verified by flow linear dichroism techniques. Both enantiomers cause a reversible unwinding by the formation of noncovalent intercalative complexes. The effects of covalently bound BPDE residues on the electrophoretic mobilities of the RF I DNA form in agarose gels were investigated in detail in the range of binding ratios rb approximately 0.0-0.06 (covalently bound BPDE residues/nucleotide). In this range of rb values, there is a striking difference in the mobilities of (+)-BPDE- and (-)-BPDE-adducted phi X174 DNA in agarose slab-gels, the covalently bound (+)-BPDE residues causing a significantly greater retardation than (-)-BPDE residues. Increasing the level of covalent adducts beyond rb approximately 0.06 in the case of the (+)-BPDE enantiomer, leads to further unwinding and a minimum in the mobilities (corresponding to comigration of the nicked form and the covalently closed relaxed modified form) at rb 0.10 +/- 0.01; at still higher rb values, rewinding of the modified DNA in the opposite sense is observed. From the minimum in the mobility, a mean unwinding angle (per BPDE residue) of theta = 12 +/- 1.5 degrees is determined, which is in good agreement the value of theta = 11 +/- 1.8 degrees obtained by the tube gel titration method. Using this latter method, values of theta = 6.8 +/- 1.7 degrees for (-)-BPDE-phi X174 adducts are observed. It is concluded that agarose slab gel techniques are not suitable for determining unwinding angles for (-)-BPDE-modified phi X174 DNA because the alterations in the tertiary structures for rb < 0.06 are too small to cause sufficiently large changes in the electrophoretic mobilities. The major trans (+)-BPDE-N2-guanosine covalent adduct is situated at external binding sites and the mechanisms of unwinding are therefore different from those relevant to noncovalent intercalative BPDE-DNA complexes or to classical intercalating drug molecules; a flexible hinge joint and a widening of the minor groove at the site of the lesion may account for the observed unwinding effects. The more heterogeneous (-)-BPDE-nucleoside adducts (involving cis and trans N2-guanosine, and adenosine adducts) are less effective in causing unwinding of supercoiled DNA for reasons which remain to be elucidated.

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“…All reactions were carried out under pseudo-first-order conditions with concentrations of diol epoxides and epoxides in the range 10 -6 to 10 -7 M. Overall, pseudo-first-order rate constants of BPDE, BADE, BPO, and BAO were obtained by measuring the increase in fluorescence intensity which occurs as products are formed. The epoxides have negligible fluorescence intensities compared to the DNA adducts or to the hydrolysis and rearrangement products (6,7,18). Excitation wavelengths used to monitor BPDE, BADE, BPO, and BAO reactions were 350, 365, 330, and 310 nm, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…1 Abbreviations: BA, benz[a]anthracene; BA34D, trans-3,4-dihydroxy-3,4-dihydro-BA; BA56D, cis-5,6-dihydroxy-5,6-dihydro-BA; BADE, (()-trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tetrahydro-BA; BAO, (()-BA-5,6-oxide; BA tetrol, 1,2,3,4-tetrahydroxy-1,2,3,4-tetrahydro-BA; BP, benzo[a]pyrene; BP45D, trans-4,5-dihydroxy-4,5-dihydro-BP; BP78D, trans-7,8-dihydroxy-7,8-dihydro-BP; BPDE, (()-trans-7,8-dihydroxyanti-9,10-epoxy-7,8,9,10-tetrahydro-BP; BPO, (()-BP-4,5-oxide; BP tetrol, 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydro-BP; ctDNA, calf thymus DNA; 5-OH-BA, 5-hydroxy-BA; 6-OH-BA, 6-hydroxy-BA; 4-OH-BP, 4-hydroxy-BP; 5-OH-BP, 5-hydroxy-BP; PAH, polycyclic aromatic hydrocarbon; poly(A), poly(riboadenylic acid); poly(C), poly(ribocytidylic acid); poly(G), poly(riboguanylic acid); poly(I), poly(riboinosinic acid); poly(U), poly(ribouridylic acid). BADE, like BPDE, forms DNA adducts and hydrolyzes (18). The hydrolysis product is 1,2,3,4-tetrahydroxy-1,2,3,4-tetrahydro-BA (BA tetrol).…”

Section: Introductionmentioning

confidence: 99%

Influence of Na⁺ on DNA Reactions with Aromatic Epoxides and Diol Epoxides: Evidence That DNA Catalyzes the Formation of Benzo[a]pyrene and Benz[a]anthracene Adducts at Intercalation Sites

Fernando

Huang

Milliman

et al. 1996

Chem. Res. Toxicol.

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Reactions of the benzo[a]pyrene (BP) and benz[a]anthracene (BA) metabolites, (+/-)-trans-7 8-dihydroxy-anti-9, 10-epoxy-7, 8, 9, 10-tetrahydro-BP (BPDE), (+/-)-trans-3, 4-dihydroxy-anti- 1,2-epoxy-1,2,3,4-tetrahydro-BA (BADE), (+/-)-BP-4,5-oxide (BPO), and (+/-)-BA-5, 6-oxide (BAO), were examined under pseudo-first-order conditions at varying Na+ (2.0-100 Mm) and native calf thymus DNA (ctDNA) concentrations. In 0.2 mM ctDNA and 2.0 mM Na+, at a pH of 7.3 most BPDE, BADE, BPO, and BAO (87-95%) undergo DNA catalyzed hydrolysis or rearrangement. For BPDE and BPO, overall, pseudo-first-order rate constants, k, in 2.0 mM Na+ and 0.2 mM ctDNA are 21-72 times larger than values obtained without DNA. For BADE and BAO, the rate constants are less strongly influenced by DNA; k values in 0.2 mM ctDNA are only 9-12 times larger than values obtained without DNA. Kinetic data for BPDE, BPO, BADE, and BAO and DNA intercalation association constants (KA) for BP and BA diols which are model compounds indicate that KA values for BPDE and BPO in 2.0 mM Na+ are 6.6-59 times larger than those of BADE and BAO. The greater DNA enhancement of rate constants for BPDE and BPO, versus BADE and BAO, correlates with the larger KA values of the BP metabolites. DNA adducts, which account for less than 10% of the yields, also form. For BPDE in 0.20 mM ctDNA, k decreases 5.1 times as the Na+ concentration increases from 2.0 to 100 mM. Nevertheless, the DNA adduct level remains constant over the range of Na+ concentrations examined. These results provide evidence that, for BPDE in 0.20 mM DNA and 2.0 mM Na+, ctDNA adduct formation follows a mechanism which is similar to that for DNA catalyzed hydrolysis. The pseudo-first-order rate constant for adduct formation, kAd, given approximately by kAd approximately equal to (kcat,AdKA[DNA])/(1 + KA[DNA]), where kcat,Ad is a catalytic rate constant. for BADE, BPO, and BAO, the influence of varying DNA and Na+ concentrations on k values is similar to that for BPDE, and provides evidence that the formation of adducts follows the same rate law.

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Reactions of stereoisomeric and structurally related bay region diol epoxide derivatives of benz[a]anthracene with DNA. Conformations of non-covalent complexes and covalent carcinogen-DNA adducts

Cited by 10 publications

References 37 publications

Solvolysis of the bay region diol epoxides of 7-methylbenz[c]acridine in aqueous solution and effect of DNA

Solvolysis of the bay region diol epoxides of 7-methylbenz[c]acridine in aqueous solution and effect of DNA

Differences in unwinding of supercoiled DNA induced by the two enantiomers ofanti-benzo[a]pyrene diol epoxide

Influence of Na⁺ on DNA Reactions with Aromatic Epoxides and Diol Epoxides: Evidence That DNA Catalyzes the Formation of Benzo[a]pyrene and Benz[a]anthracene Adducts at Intercalation Sites

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Reactions of stereoisomeric and structurally related bay region diol epoxide derivatives of benz[a]anthracene with DNA. Conformations of non-covalent complexes and covalent carcinogen-DNA adducts

Cited by 10 publications

References 37 publications

Solvolysis of the bay region diol epoxides of 7-methylbenz[c]acridine in aqueous solution and effect of DNA

Solvolysis of the bay region diol epoxides of 7-methylbenz[c]acridine in aqueous solution and effect of DNA

Differences in unwinding of supercoiled DNA induced by the two enantiomers ofanti-benzo[a]pyrene diol epoxide

Influence of Na+ on DNA Reactions with Aromatic Epoxides and Diol Epoxides: Evidence That DNA Catalyzes the Formation of Benzo[a]pyrene and Benz[a]anthracene Adducts at Intercalation Sites

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Influence of Na⁺ on DNA Reactions with Aromatic Epoxides and Diol Epoxides: Evidence That DNA Catalyzes the Formation of Benzo[a]pyrene and Benz[a]anthracene Adducts at Intercalation Sites