Synthesis and mutagenicity of the diastereomeric fjord-region 11,12-dihydrodiol 13,14-epoxides of dibenzo [<i>a,l</i>]pyrene

Luch, Andreas; Glatt, Hansruedi; Platt, Karl L.; Oesch, Franz; Seidel, Albrecht

doi:10.1093/carcin/15.11.2507

Cited by 96 publications

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“…In all five of the test systems, these compounds were much more potent than any of the bay or fjord region diol-epoxides tested before (29,55). The specific mutagenicity observed with anti-DB[a,l]PDE in strain TA104 exhibited the highest value ever found with any compound in any his-strains of S. typhimurium.…”

Section: Discussionmentioning

confidence: 90%

“…The mutagenicity of racemic syn-and anti-DB[a,l]PDE was examined in four his-strains of Salmonella typhimurium and in Chinese hamster V79 cells (29). In all five of the test systems, these compounds were much more potent than any of the bay or fjord region diol-epoxides tested before (29,55).…”

Section: Discussionmentioning

confidence: 99%

“…After centrifugation, the pellet (exclusive of cartilage and bones) was resuspended and fibroblasts were cultured in DMEM containing 10% fetal bovine serum. (ϩ)-Syn-and (Ϫ)-anti-DB[a,l]PDE were synthesized as described (29,37,38).…”

Section: Methodsmentioning

confidence: 99%

“…27, 28). Racemic syn-and anti-DB [a,l]PDE are extraordinary potent mutagens in both prokaryotic and eukaryotic test systems (29) and potent carcinogens in the rat mammary gland (30). The strong mutagenicity of these compounds may partly result from an increased resistance to enzymatic repair of the lesions induced.…”

Section: Introductionmentioning

confidence: 99%

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DNA Damage, Repair, and Mutation Induction by (+)- Syn and (−)- Anti -Dibenzo[ a,l ]Pyrene-11,12-Diol-13,14-Epoxides in Mouse Cells

et al. 2004

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA Damage, Repair, and Mutation Induction by (+)- Syn and (−)- Anti -Dibenzo[ a,l ]Pyrene-11,12-Diol-13,14-Epoxides in Mouse Cells

et al. 2004

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“…Recent in vivo studies with rodents have shown that at low doses the tumor-initiating activity of DB[a,l]P is significantly greater than that of benzo[a]pyrene or 7,12-dimethylbenz [a]anthracene (4)(5)(6). DB[a,l]P, like other PAHs, can be enzymatically activated to electrophilic intermediates that bind to DNA (7,8); formation of covalent DNA adducts is believed to be responsible for the mutagenic and carcinogenic activity of DB[a,l]P (7,9,10). 32 P-Postlabeling analysis of DB-[a,l]P-DNA adducts has shown that metabolic activation of DB[a,l]P in cell cultures occurs via formation of the fjord region 11,12-diol 13,14-epoxide (DE) intermediates, which can in principle exist in four different stereoisomeric forms (4,11).…”

Section: Introductionmentioning

confidence: 99%

Conformational Studies of Stereoisomeric Tetrols Derived from syn- and anti-Dibenzo[a,l]pyrene Diol Epoxides

Jankowiak

Ariese

Zamzow

et al. 1997

Chem. Res. Toxicol.

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An understanding of the conformational behavior of the stereoisomeric tetrols at the 11,12,13,14-positions of dibenzo [a,l]pyrene (DB[a,l]P) is essential for the spectroscopic identification of DNA adducts derived from the biologically highly active fjord region syn-and anti-DB [a, [829][830][831][832][833][834][835][836][837] 1996). Molecular mechanics, dynamical simulations, and semiempirical calculations of electronic transitions are used to interpret the low-temperature fluorescence spectra and 1 H NMR data. Molecular dynamics simulations (in vacuo) identified two conformers (I and II) for each of the tetrol isomers; in all conformations the aromatic ring system is severely distorted. Fluorescence line-narrowing (FLN) spectroscopy identified two distinct conformational species for the transanti isomer, one occurring in ethanol and the other occurring in a glycerol/water matrix. The corresponding structures are assigned based on the S 1 r S 0 transition energies calculated for conformers I and II, respectively. 1 H NMR spectroscopy confirmed the structure of conformer I at room temperature. In contrast to trans-syn-DB [a,l]P tetrol (where the major conformation was identified as a boat structure), both conformations of trans-anti-DB[a,l]P tetrol feature a half-chair structure for the cyclohexenyl ring with different orientations of the hydroxyl groups. For cis-anti-and cis-syn-DB [a,l]P tetrols, only a single conformer is detected by FLN spectroscopy. The NMR results for the latter appear to be most consistent with a mixture of two half-chair conformers I and II, while for the cis-anti isomer a flattened, boatlike conformation was observed. The generally good agreement between the NMR coupling constants and those estimated theoretically indicates that these structures should serve as good starting points for spectroscopic or computational studies of DNA adducts derived from DB[a,l]P diol epoxides.

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A quantitative comparison of dibenzo[a,l]pyrene-DNA adduct formation by recombinant human cytochrome P450 microsomes

et al. 1999

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Dibenzo[a,l]pyrene (DB[a,l]P), an extremely potent environmental carcinogen, is metabolically activated in mammalian cells and microsomes through the fjord-region dihydrodiol, trans-DB[a,l]P-11, 12-diol, to syn- and anti-DB[a,l]P-11,12-diol-13,14-epoxides (syn- and anti-DB[a,l]PDEs). The role of seven individual recombinant human cytochrome P450s (1A1, 1A2, 1B1, 2B6, 2C9, 2E1, and 3A4) in the metabolic activation of DB[a,l]P and formation of DNA adducts was examined by using (32)P postlabeling, thin-layer chromatography, and high-pressure liquid chromatography. We found that, in the presence of epoxide hydrolase, only P450 1A1 and P450 1B1 catalyzed the formation of DB[a,l]PDE-DNA adducts and several unidentified polar adducts. Human P450 1A1 catalyzed the formation of DB[a, l]PDE-DNA adducts and unidentified polar adducts at rates threefold and 17-fold greater than did human P450 1B1 (256 fmol/h/nmol P450 versus 90 fmol/h/nmol P450 and 132 fmol/h/nmol P450 versus 8 fmol/h/nmol P450, respectively). P450 1A1 DNA adducts were derived from both anti- and syn-DB[a,l]PDE at rates of 73 fmol/h/nmol P450 and 51 fmol/h/nmol P450, respectively. P450 1B1 produced adducts derived from anti-DB[a,l]PDE at a rate of 82 fmol/h/nmol, whereas only a small number of adducts were derived from syn-DB[a,l]PDE (0.4 fmol/h/nmol). These results demonstrated the potential of human P450 1A1 and P450 1B1 to contribute to the metabolic activation and carcinogenicity of DB[a,l]P and provided additional evidence that human P450 1A1 and 1B1 differ in their stereospecific activation of DB[a,l]P. Mol. Carcinog. 26:74-82, 1999. Published 1999 Wiley-Liss, Inc.

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Synthesis and mutagenicity of the diastereomeric fjord-region 11,12-dihydrodiol 13,14-epoxides of dibenzo [a,l]pyrene

Cited by 96 publications

References 0 publications

DNA Damage, Repair, and Mutation Induction by (+)- Syn and (−)- Anti -Dibenzo[ a,l ]Pyrene-11,12-Diol-13,14-Epoxides in Mouse Cells

DNA Damage, Repair, and Mutation Induction by (+)- Syn and (−)- Anti -Dibenzo[ a,l ]Pyrene-11,12-Diol-13,14-Epoxides in Mouse Cells

Conformational Studies of Stereoisomeric Tetrols Derived from syn- and anti-Dibenzo[a,l]pyrene Diol Epoxides

A quantitative comparison of dibenzo[a,l]pyrene-DNA adduct formation by recombinant human cytochrome P450 microsomes

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