Structure Elucidation of the Adducts Formed by Fjord-Region Dibenzo[<i>a</i>,<i>l</i>]pyrene 11,12-Dihydrodiol 13,14-Epoxides and Deoxyadenosine

Li, Kaiming; George, M. C.; Gross, Michael L.; Seidel, Albrecht; Luch, Andreas; Rogan, Eleanor G.; Cavalieri, Ercole L.

doi:10.1021/tx980197x

Cited by 14 publications

(47 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is supported by the CD spectra of these adducts: Our adduct dAMP 3(-) has a CD spectrum below 300 nm practically identical to that of adduct L4 of Li et al that also arises from the (-) enantiomer. Similarly, our adduct dAMP 4(+) resembles in all respects adduct L3 of Li et al In summary, if we take this difference in elution orders into account, our CD spectra of the adducts arising from either (+)-anti-DB[a,l]PDE or the (-)-enantiomer are identical to those of the analogous adducts described by Li et al (12).…”

Section: Discussionsupporting

confidence: 78%

“…There are, however, complications because at least two different benzylic ring conformations have been observed in the anti-DB[a,l]-PDE-N 6 -dA adducts by fluorescence (63) and NMR methods (12). A substantial body of NMR data on PAH dihydrodiol epoxide-deoxyribonucleoside adducts, including adducts derived from fjord PAH derivatives, has been accumulated [reviewed by Szeliga and Dipple (13)].…”

Section: Discussionmentioning

confidence: 99%

“…The CD spectra of each of the four adducts is depicted in Figure 2. Clearly, there are two pairs of diastereomeric adducts with similar CD spectra that are opposite in sign (12). To identfy these four adducts further, similar reactions with dAMP were carried out with the optically pure (+)-anti-DB[a,l]PDE and (-)-anti-DB[a,l]PDE enantiomers.…”

Section: Synthesis and Identification Of Mononucleotide Adducts Derivmentioning

confidence: 99%

“…Fraction 3 was subjected to a further HPLC separation that resulted in fractions 3A and 3B (insert, To determine the stereochemical characteristics of the modified bases in these four oligonucleotides, the double stranded forms used in the UV melting studies (see below) were digested to the nucleotide levels using a combination of DNAse I, Nuclease P1, and SVPD. The HPLC elution times and CD spectra of these mononucleotide adducts were then compared to those of anti-DB-[a,l]PDE-N 6 -dAMP adduct standards using approaches described in the literature (12,17).…”

Section: Synthesis and Identification Of Oligonucleotides Modified Bymentioning

confidence: 99%

See 3 more Smart Citations

Synthesis and Characterization of Site-Specific and Stereoisomeric Fjord Dibenzo[a,l]pyrene Diol Epoxide−N⁶-Adenine Adducts: Unusual Thermal Stabilization of Modified DNA Duplexes

Ruan

Kolbanovskiy

Zhuang

et al. 2002

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The fjord polycyclic aromatic hydrocarbon compound dibenzo[a,l]pyrene (DB[a,l]P) is significantly more tumorigenic than the bay region benzo[a]pyrene in animal model systems. The molecular origins of the unusually strong genotoxic properties of DB[a,l]P and its fjord region diol epoxide metabolites are of great interest and are believed to be related to the structural characteristics of the DNA adducts formed. Site-specifically modified oligonucleotides were prepared by reacting the single adenine residue in 5'-d(CTCTCACTTCC) (I) with the racemic fjord diol epoxide r11,t12-dihydrodiol-t13,14-epoxide-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (anti-DB[a,l]PDE) in aqueous solutions. Four different oligonucleotides I with the single adenosine residues involving a covalent bond between the C14 position of DB[a,l]PDE and N(6)-dA are identified and purified. The CD spectra of the mononucleotide adducts are similar to those of Li et al. [Li et al. (1999) Chem. Res. Toxicol. 12, 758] who characterized DB[a,l]PDE-N(6)-dA adducts by a combination of CD and NMR methods. The stereochemical properties of each of the four DB[a,l]PDE-modified oligonucleotides were assigned on the basis of a combination of empirical CD rules and other approaches and differ from those of Li et al. The thermal melting points, T(m), of the unmodified duplex of I with its complementary strand (IC), T(m) = 43.8 +/- 0.5 degrees C, were compared with the same duplexes containing stereoisomeric anti-DB[a,l]PDE-N(6)-dA lesions. The T(m) of duplexes I.IC containing lesions with R absolute configurations at C14 of the DB[a,l]PDE residues are greater by 6-8 degrees C, while those with S configuration are lower by 6-10 degrees C. Similar effects are observed with adducts in the same sequence context derived from the fjord PAH anti-diol epoxides of benzo[g]chrysene, while duplexes containing lesions derived from benzo[c]phenanthrene diol epoxides with 1R and 1S configurations exhibit unchanged T(m) values. In contrast, the T(m) values of duplexes with lesions derived from the bay region benzo[a]pyrene diol epoxides (B[a]PDE) in the same sequence are lower by 12 degrees (10R adducts) and by 19 degrees (10S adducts). The greater thermal stabilities of duplexes with fjord PAH-N(6)-dA lesions relative to those with bay region B[a]PDE-N(6)-dA adducts, are correlated with lower susceptibilities of excision by human nucleotide excision repair enzymes [Buterin et al. (2000) Cancer Res. 60, 1849]. The implications of these relationships are discussed in terms of present knowledge of the conformations of fjord and bay region PAH diol epoxide-N(6)-dA lesions in double stranded DNA.

show abstract

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Synthesis and Identification Of Mononucleotide Adducts Derivmentioning

confidence: 99%

Section: Synthesis and Identification Of Oligonucleotides Modified Bymentioning

confidence: 99%

See 2 more Smart Citations

Synthesis and Characterization of Site-Specific and Stereoisomeric Fjord Dibenzo[a,l]pyrene Diol Epoxide−N⁶-Adenine Adducts: Unusual Thermal Stabilization of Modified DNA Duplexes

Ruan

Kolbanovskiy

Zhuang

et al. 2002

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…DMF was then removed under vacuum; the residue was dissolved in DMSO/CH 3 OH (1:1). The adducts were purified on a reversed-phase YMC ODS-AQ 5 µm, 120 Å column (6.0 mm × 250 mm) (YMC, Wilmington, NC), using a CH 3 CN/H 2 O gradient, following the methods reported by Li et al (21). Each eluted fraction was further purified by 70% isocratic CH 3 OH/H 2 O using the same column (21).…”

Section: Methodsmentioning

confidence: 99%

Identification and Quantification of DNA Adducts in the Oral Tissues of Mice Treated with the Environmental Carcinogen Dibenzo[a,l]pyrene by HPLC-MS/MS

Zhang

Chen

Aliaga

et al. 2011

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Tobacco smoking is one of the leading causes for oral cancer. Dibenzo[a,l]pyrene (DB[a,l]P), an environmental pollutant and a tobacco smoke constituent, is the most carcinogenic polycyclic aromatic hydrocarbon (PAH) tested to date in several animal models (target organs: skin, lung, ovary and mammary tissues). We have recently demonstrated that DB[a,l]P is also capable of inducing oral cancer in mice; however its metabolic activation to the ultimate genotoxic metabolite dibenzo[a,l]pyrene-11,12-dihydrodiol-13,14-epoxide (DB[a,l]PDE) in mouse oral cavity has not been examined. Here we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to detect and quantify (±)-anti-DB[a,l]PDE-dA adducts in oral tissues of mice treated with DB[a,l]P. [15N5]-(±)-anti-DB[a,l]PDE-N6-dA adducts were synthesized as internal standards. The stereoisomeric adducts were characterized by MS, NMR and CD analysis. The detection limit of the method is 8 fmol with 100 µg digested DNA as the matrix. Two adducts were detected and identified as (−)-anti-cis and (−)-anti-trans-DB[a,l]PDE-dA in the oral tissues of mice following direct application of DB[a,l]P (240 nmol per day, for 2 days) into the oral cavity, indicating that DB[a,l]P is predominantly metabolized into (−)-anti-DB[a,l]PDE in this target organ. We also compared the formation and removal of adducts as a function of time, following direct application of DB[a,l]P (24 nmol, 3 times per week for 5 weeks) into the oral cavity of mice. Adducts were quantified at 48 h, 1, 2 and 4 weeks after the last dose. Maximal levels of adducts occurred at 48 h, followed by a gradual decrease. The levels (fmol/µg DNA) of (−)-anti-trans adducts (4.03±0.27 to 1.77±0.25) are significantly higher than (−)-anti-cis-DB[a,l]PDE-dA adduct (1.63±0.42 to 0.72±0.04) at each time point (p < 0.005). The results presented here indicate that the formation and persistence of (−)-anti-DB[a,l]PDE-dA adducts may, in part, contribute to the initiation of DB[a,l]P-induced oral carcinogenesis.

show abstract

Role of Fluorescence Line-Narrowing Spectroscopy and Related Luminescence-Based Techniques in the Elucidation of Mechanisms of Tumor Initiation by Polycyclic Aromatic Hydrocarbons and Estrogens

2004

Self Cite

View full text Add to dashboard Cite

Formation of DNA adducts by various carcinogens represents the first critical event in the mechanism of tumor initiation. The carcinogenic polycyclic aromatic hydrocarbons (PAHs) are biologically activated by two major mechanisms: one-electron oxidation to produce radical cations and monooxygenation to form bay-region diol epoxides. The PAH-DNA adducts formed by these mechanisms are stable adducts that remain in DNA unless removed by repair and depurinating adducts that are lost from DNA by cleavage of the glycosyl bond. Identification of PAH-DNA adducts has relied heavily on low-temperature, laser-based fluorescence spectroscopy under non-line-narrowing (NLN) and line-narrowing (FLN) conditions. These spectroscopies can be used for chemical identification, conformational analysis, and/or probing the microenvironment of DNA (or protein) adducts. Small and co-workers have pioneered the use of FLN spectroscopy in this research. For example, the structures of the depurinating adducts formed by the PAHs benzo[a]pyrene, 7,12dimethylbenz[a]anthracene, and dibenzo[a,l]pyrene have been elucidated. Understanding of the mechanism of tumor initiation by PAHs has relied on identifying and quantifying the DNA adducts formed. The insights gained from the study of PAH-DNA adducts enabled us to discover the estrogen metabolites that form depurinating DNA adducts and can be potential endogenous initiators of human cancer. Small and co-workers have also studied the estrogen-DNA adducts and estrogen-thioether conjugates by using FLNS and related luminescence-based techniques and have demonstrated that the level of the 4-hydroxyestrone-1-N3-adenine depurinating adduct in breast tissue from a woman with breast carcinoma was significantly higher than that in breast tissue from women without breast cancer. The fluorescence-and phosphorescence-based techniques they are developing will be applied to analyzing estrogen adducts and conjugates as biomarkers of susceptibility to breast and other types of human cancer.

show abstract

Structure Elucidation of the Adducts Formed by Fjord-Region Dibenzo[a,l]pyrene 11,12-Dihydrodiol 13,14-Epoxides and Deoxyadenosine

Cited by 14 publications

References 18 publications

Synthesis and Characterization of Site-Specific and Stereoisomeric Fjord Dibenzo[a,l]pyrene Diol Epoxide−N⁶-Adenine Adducts: Unusual Thermal Stabilization of Modified DNA Duplexes

Synthesis and Characterization of Site-Specific and Stereoisomeric Fjord Dibenzo[a,l]pyrene Diol Epoxide−N⁶-Adenine Adducts: Unusual Thermal Stabilization of Modified DNA Duplexes

Identification and Quantification of DNA Adducts in the Oral Tissues of Mice Treated with the Environmental Carcinogen Dibenzo[a,l]pyrene by HPLC-MS/MS

Role of Fluorescence Line-Narrowing Spectroscopy and Related Luminescence-Based Techniques in the Elucidation of Mechanisms of Tumor Initiation by Polycyclic Aromatic Hydrocarbons and Estrogens

Contact Info

Product

Resources

About

Structure Elucidation of the Adducts Formed by Fjord-Region Dibenzo[a,l]pyrene 11,12-Dihydrodiol 13,14-Epoxides and Deoxyadenosine

Cited by 14 publications

References 18 publications

Synthesis and Characterization of Site-Specific and Stereoisomeric Fjord Dibenzo[a,l]pyrene Diol Epoxide−N6-Adenine Adducts: Unusual Thermal Stabilization of Modified DNA Duplexes

Synthesis and Characterization of Site-Specific and Stereoisomeric Fjord Dibenzo[a,l]pyrene Diol Epoxide−N6-Adenine Adducts: Unusual Thermal Stabilization of Modified DNA Duplexes

Identification and Quantification of DNA Adducts in the Oral Tissues of Mice Treated with the Environmental Carcinogen Dibenzo[a,l]pyrene by HPLC-MS/MS

Role of Fluorescence Line-Narrowing Spectroscopy and Related Luminescence-Based Techniques in the Elucidation of Mechanisms of Tumor Initiation by Polycyclic Aromatic Hydrocarbons and Estrogens

Contact Info

Product

Resources

About

Synthesis and Characterization of Site-Specific and Stereoisomeric Fjord Dibenzo[a,l]pyrene Diol Epoxide−N⁶-Adenine Adducts: Unusual Thermal Stabilization of Modified DNA Duplexes

Synthesis and Characterization of Site-Specific and Stereoisomeric Fjord Dibenzo[a,l]pyrene Diol Epoxide−N⁶-Adenine Adducts: Unusual Thermal Stabilization of Modified DNA Duplexes