The synthesis of dibenzo[a,l]pyrene

Vingiello, Frank A.; Yanez, Jose; Greenwood, Edward James

doi:10.1039/c1966000375a

Cited by 5 publications

(5 citation statements)

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“…Before 1966, the chemical listed in the literature as DBalP (1,2,3,4-dibenzopyrene) was in fact dibenzo[a,e]fluoranthene [ 56 ]. Cavalieri et al [ 36 ] noted that synthesis of DBalP by Vingiello et al [ 57 ] and Carruthers [ 58 ] occurred in 1966; it was subsequently tested in 1968 by subcutaneous injection in mice, and found to induce sarcomas [ 55 ]. Devanesan et al [ 59 ] indicated that any carcinogenicity tests prior to 1968 had incorrectly used the weakly active DBaeF instead of DBalP.…”

Section: Resultsmentioning

confidence: 99%

The Long Goodbye: Finally Moving on from the Relative Potency Approach to a Mixtures Approach for Polycyclic Aromatic Hydrocarbons (PAHs)

Haber

Pecquet

Vincent

et al. 2022

IJERPH

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For the past several decades, a relative potency approach has been used to estimate the human health risks from exposure to polycyclic aromatic hydrocarbon (PAH) mixtures. Risk estimates are derived using potency equivalence factors (PEFs; also called relative potency factors [RPFs]), based on the ratio of selected PAHs to benzo[a]pyrene (BaP), expressed qualitatively by orders of magnitude. To quantify PEFs for 18 selected carcinogenic PAHs, a systematic approach with a priori and dose response criteria was developed, building on draft work by the US EPA in 2010 and its review by US EPA Science Advisory Board (SAB) in 2011. An exhaustive search for carcinogenicity studies that included both target PAHs and BaP with environmentally relevant exposure routes found only 48 animal bioassay datasets (mostly pre-1992 based on skin painting). Only eight datasets provided adequate low-response data, and of these only four datasets were appropriate for modeling to estimate PEFs; only benzo[b]fluoranthene and cyclopenta[c,d]pyrene had a PEF that could be quantified. Thus, current knowledge of PAH carcinogenicity is insufficient to support quantitative PEFs for PAH mixtures. This highlights the long-acknowledged need for an interdisciplinary approach to estimate risks from PAH mixtures. Use of alternative and short-term toxicity testing methods, improved mixture characterization, understanding the fate and bioavailability of PAH mixtures, and understanding exposure route-related differences in carcinogenicity are discussed as ways to improve the understanding of the risks of PAHs.

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Section: Resultsmentioning

confidence: 99%

The Long Goodbye: Finally Moving on from the Relative Potency Approach to a Mixtures Approach for Polycyclic Aromatic Hydrocarbons (PAHs)

Haber

Pecquet

Vincent

et al. 2022

IJERPH

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“…The stereochemistry and the amount of fjord region DB[ a,l ]PDE enzymatically formed from the (+)-(11 S ,12 S )- and (−)-(11 R ,12 R )-dihydrodiol were determined by measuring the tetrols as hydrolysis products of the dihydrodiol epoxides. Racemic tetrols, synthesized as described before, were suitable for an unequivocal elucidation of the stereochemistry involved in the formation of fjord region DB[ a,l ]PDE from the enantiomeric dihydrodiols (Scheme ) since they are chromatographically indistinguishable from their enantiomers when separated by HPLC on achiral stationary phases. According to the findings for the fjord region B[ c ]PhDE (), the syn -DB[ a,l ]PDE was hydrolyzed upon acidic workup (pH 2−3) of control incubations without microsomes by trans - and cis -attack of water to a 1:4 mixture of the ( r,t,c,t )- and ( r,t,c,c )-tetrols (Scheme ), while acidic hydrolysis of the anti -DB[ a,l ]PDE yielded exclusively the trans -opened product, the ( r,t,t,c )-tetrol.…”

Section: Resultsmentioning

confidence: 99%

“…Synthesis of Racemic Metabolites of DB[ a,l ]P. The synthesis of the (±)-11,12-dihydrodiol of DB[ a,l ]P and the two diastereomeric syn - and anti -DB[ a,l ]PDE was performed by a pathway published earlier (). The tetrols required as reference compounds were obtained by hydrolysis of the diastereomeric syn - and anti -DB[ a,l ]PDE in an acidic solution of 1,4-dioxane/water (containing 1−2 drops of concentrated hydrochloric acid) and subsequent separation by HPLC as previously described …”

Section: Methodsmentioning

confidence: 99%

“…As calculated from the earlier experiments employing the 3 H-labeled (()-11,12-dihydrodiol, the metabolic conversion of this substrate increases even after long incubation times due to an extraordinarily low but constant total turnover rate of 0.34 ( 0.16 nmol/(nmol of P450‚ min). 2 Interestingly, already after 10 min of incubation of both 11,12-dihydrodiol enantiomers the amounts of tetrols derived from the syn-DB[a,l]PDE seem to remain nearly constant or slightly decreases. In contrast, the amount of the corresponding (-)-anti-DB[a,l]PDE formed from the (-)-dihydrodiol increases to high excesses dependening on the incubation time (Table 1).…”

Section: Incubation Of Racemic or Enantiomericallymentioning

confidence: 99%

“…The first synthesis and physicochemical characterization of the peri-condensed hexacyclic aromatic hydrocarbon dibenzo[ a,l ]pyrene (DB[ a,l ]P) (Scheme ) had been unequivocally achieved in 1966 ( , ). Indications about the extraordinary strong carcinogenic activity of this polycyclic aromatic hydrocarbon (PAH) were obtained after its topical administration on mice skin in an early carcinogenicity study ().…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Activation of the (+)-S,S- and (−)-R,R-Enantiomers of trans-11,12-Dihydroxy-11,12-dihydrodibenzo[a,l]pyrene: Stereoselectivity, DNA Adduct Formation, and Mutagenicity in Chinese Hamster V79 Cells

Luch¹,

Seidel²,

Glatt³

et al. 1997

Chem. Res. Toxicol.

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Polycyclic aromatic hydrocarbons require metabolic activation in order to exert their biological activity initiated by DNA binding. The metabolic pathway leading to bay or fjord region dihydrodiol epoxides as ultimate mutagenic and/or carcinogenic metabolites is thought to play a dominant role. For dibenzo[a,l]pyrene, considered as the most potent carcinogenic polycyclic aromatic hydrocarbon, the formation of the fjord region syn- and/or anti-11,12-dihydrodiol 13,-14-epoxide (DB[a,l]PDE) diastereomers has been found to be the principal metabolic activation pathway in cell cultures leading to DNA adducts. In order to further elucidate the stereoselectivity involved in this activation pathway via the formation of the trans-11,12-dihydrodiol, we have synthesized the enantiomerically pure 11,12-dihydrodiols of dibenzo[a,l]-pyrene and investigated their biotransformation in rodents. Incubations with liver microsomes of Sprague-Dawley rats and CD-1 mice pretreated with Aroclor 1254 revealed that the enzymatic conversion to the fjord region DB[a,l]PDE strongly depends on the absolute configuration of the 11,12-dihydrodiol enantiomers. While oxidation at the 13,14-position of the (+)-(11S,12S)-dihydrodiol is limited to a small extent, the (-)-11R,12R-enantiomer is metabolized to its fjord region dihydrodiol epoxides in considerably higher amounts. Moreover, this substrate is transformed with high stereoselectivity to the corresponding (-)-anti-dihydrodiol epoxide by liver microsomes of Aroclor 1254-treated rodents. The metabolism results were in good accordance with the extent of stable adduct formation in calf thymus DNA as investigated by the 32P-postlabeling technique and with the mutagenicity in Chinese hamster V79 cells of the two enantiomeric 11,12-dihydrodiols mediated by hepatic postmitochondrial preparations of Aroclor 1254-treated rats. The results indicate that both genotoxic events occurred predominantly by the stereoselective activation of the (-)-(11R,12R)-dihydrodiol to the (-)-anti-DB[a,l]PDE with R,S,S,R-configuration.

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On the impact of the molecule structure in chemical carcinogenesis

Luch

2009

Experientia Supplementum

101

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The synthesis of dibenzo[a,l]pyrene

Cited by 5 publications

References 0 publications

The Long Goodbye: Finally Moving on from the Relative Potency Approach to a Mixtures Approach for Polycyclic Aromatic Hydrocarbons (PAHs)

The Long Goodbye: Finally Moving on from the Relative Potency Approach to a Mixtures Approach for Polycyclic Aromatic Hydrocarbons (PAHs)

Metabolic Activation of the (+)-S,S- and (−)-R,R-Enantiomers of trans-11,12-Dihydroxy-11,12-dihydrodibenzo[a,l]pyrene: Stereoselectivity, DNA Adduct Formation, and Mutagenicity in Chinese Hamster V79 Cells

On the impact of the molecule structure in chemical carcinogenesis

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