Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Buening, Mildred K.; Wislocki, Peter G.; Levin, Wayne; Yagi, Haruhiko; Thakker, Dhiren R.; Akagi, H.; Koreeda, Masato; Jerina, Donald M.; Conney, Allan H.

doi:10.1073/pnas.75.11.5358

Cited by 371 publications

(158 citation statements)

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“…Although a weak complete carcinogen on mouse skin, BPDE-2 proved an extremely potent inducer of lung adenomas when inoculated intraperitoneally into newborn mice (Buening et al, 1978;Kapitulnik et al, 1978). It was 40 -50 times more active than its parental hydrocarbon, which supported its designation as the ultimate carcinogen of BP but leaves unresolved the question of its weak carcinogenicity on mouse skin.…”

Section: Metabolism Of Pahs and Binding To Dnamentioning

confidence: 99%

Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis

Rubin

2002

Oncogene

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Historically our knowledge about the direct carcinogenic activity of cigarette smoke and its constituents grew from painting experiments on the skin of mice to produce papillomas and carcinomas. The neutral fraction of cigarette smoke condensate had most of the carcinogenic activity in this test and was rich in carcinogenic polycyclic aromatic hydrocarbons (PAHs), the most abundant by far being BP. However, the concentration of BP in the condensate was only about 2% the amount of pure BP required to cause skin tumors. In other fractions there were non-carcinogenic constituents that promoted tumor formation when applied repeatedly to mouse skin that had been initiated by a single subcarcinogenic application of BP. There were also constituents of cigarette smoke that acted as cocarcinogens when applied simultaneously with repeated applications of BP. BP was effective as an initiator at lower concentrations than as a complete carcinogen, and some non-carcinogenic PAHs in the condensate were also active initiators. It was concluded from these studies that cigarette smoke condensate is primarily a tumorpromoting and co-carcinogenic agent with weak activity as a complete carcinogen. A major effect of promoters, and possibly of co-carcinogens, is a diffuse hyperplasia which includes selective expansion of clones carrying endogenous mutations and/or mutations induced by PAHs and other carcinogens such as NNK. The induced mutations as well as damaged cells would occur throughout the exposed region and, along with the hyperplasia, increase the permissiveness of the cellular microenvironment for neoplastic expression of any potential tumor cell in its midst. Since neither the promoters nor co-carcinogens in tobacco smoke are known to interact directly with DNA, their effects can be considered epigenetic processes that act upon genetically altered cells. Examples are cited from studies of experimental skin carcinogenesis, smoking-induced histopathological changes in human lung and spontaneous transformation in cell culture to illustrate the genetic and epigenetic interactions of neoplastic development in general and their significance for smoking-induced lung cancer in particular. Certain dietary modifications that appear to be effective in moderating the promotional phase of animal and human carcinogenesis are suggested for trial in managing lung cancer.

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Section: Metabolism Of Pahs and Binding To Dnamentioning

confidence: 99%

Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis

Rubin

2002

Oncogene

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“…Racemic anti-BPDE is reported to be more mutagenic than the diastereomer (±)-syn-BPDE [10][11][12], and the mutagenic potencies of the two anti-BPDE enantiomers are different in selected bacterial and mammalian cell systems. The (+)-anti-BPDE isomer is tumorigenic on mouse skin and in the lungs of new born mice [13,14], while the (−)-anti-BPDE enantiomer is not. In the TA100 strain, as well as in mammalian Chinese hamster ovary cells (V79 cells), the activity of the (+)-isomer is 4-6 times greater than that of (−)-anti-BPDE [15,16].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous analysis of four stereoisomers of anti-benzo[a]pyrene diol epoxide–deoxyguanosine adducts in short oligodeoxynucleotides using reversed-phase high-performance liquid chromatography

Feng

Wang

2007

Journal of Chromatography A

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Abstractanti-Benzo [a] , a reactive metabolite of the environmental carcinogen benzo[a]pyrene, predominantly binds to deoxyguanine in DNA and forms four stereoisomeric adducts. Here we developed an improved method for simultaneous analysis and purification of four stereoisomeric adducts in short oligonucleotides using reversed-phase high-performance liquid chromatography, providing a selection strategy of stationary phase for analysis and separation of polyaromatic hydrocarbon-DNA adducts. This work demonstrates that secondary retention of oligonucleotides on C18 stationary phases induced by exposed silanol heavily affects the separation of four stereosiomeric adducts on C18 stationary phases, and the silicone polymer monolayer coating for completely capping exposed silica or silanol greatly reduces such secondary retention, thereby displaying a much better resolution of the four stereoisomeric adducts. We further demonstrate that aromatic group (phenyl)-based stationary phase can significantly improve stereoisomeric separation of four anti-BPDE-deoxyguanosine (dG) adducts in short oligonucleotides over nonaromatic C18 stationary phase due to enhancement of the selective interaction with aromatic anti-BPDE moiety in oligonucleotides. The developed method was also used for purification and preparation of anti-BPDE-oligoncleotide adducts.

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“…It is converted to a highly reactive electrophilic metabolite, (ϩ)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo-[a]pyrene (B[a]P DE) (4), which can damage DNA by forming adducts, mainly at the exocyclic 2-and 6-amino groups of guanine and adenine, respectively (5). B[a]P and its diol epoxide metabolites (6)(7)(8) induce lung tumors in a newborn mouse model, and B[a]P DE-DNA adducts have been implicated in human lung cancer (9). B[c]Ph is another well studied PAH that is activated in the liver to carcinogenic diol epoxide metabolites (4).…”

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confidence: 99%

Structure of DNA polymerase β with a benzo[ c ]phenanthrene diol epoxide-adducted template exhibits mutagenic features

Batra

Shock

Prasad

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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We have determined the crystal structure of the human base excision repair enzyme DNA polymerase ␤ (Pol ␤) in complex with a 1-nt gapped DNA substrate containing a template N 2 -guanine adduct of the tumorigenic (؊)-benzo[c]phenanthrene 4R,3S-diol 2S,1R-epoxide in the gap. Nucleotide insertion opposite this adduct favors incorrect purine nucleotides over the correct dCMP and hence can be mutagenic. The structure reveals that the phenanthrene ring system is stacked with the base pair immediately 3 to the modified guanine, thereby occluding the normal binding site for the correct incoming nucleoside triphosphate. The modified guanine base is displaced downstream and prevents the polymerase from achieving the catalytically competent closed conformation. The incoming nucleotide binding pocket is distorted, and the adducted deoxyguanosine is in a syn conformation, exposing its Hoogsteen edge, which can hydrogen-bond with dATP or dGTP. In a reconstituted base excision repair system, repair of a deaminated cytosine (i.e., uracil) opposite the adducted guanine was dramatically decreased at the Pol ␤ insertion step, but not blocked. The efficiency of gap-filling dCMP insertion opposite the adduct was diminished by >6 orders of magnitude compared with an unadducted templating guanine. In contrast, significant misinsertion of purine nucleotides (but not dTMP) opposite the adducted guanine was observed. Pol ␤ also misinserts a purine nucleotide opposite the adduct with ungapped DNA and exhibits limited bypass DNA synthesis. These results indicate that Pol ␤-dependent base excision repair of uracil opposite, or replication through, this bulky DNA adduct can be mutagenic.DNA adduct ͉ DNA repair ͉ fidelity ͉ mutagenesis P olycyclic aromatic hydrocarbons (PAHs) such as benzo- , and the adduct derived from trans-opening of the epoxide ring by the exocyclic 2-amino group of guanine in DNA, which is the subject of the present investigation.Bulky PAH-derived lesions can persist in human tissues when cellular repair enzymes fail to correct these lesions (13). The presence of these lesions in the genome blocks replicative DNA polymerases. If these lesions are not repaired, they must be bypassed for replication to continue. Bypass DNA synthesis occurs when a translesional DNA polymerase is recruited to the site of DNA damage and inserts a nucleotide opposite the adduct. DNA synthesis can be error-free or error-prone. The resulting base pair is then extended by either the same DNA polymerase or an auxiliary polymerase. Because replication of these adducts is known to result in mutations (14-16), mutagenic bypass provides a mechanism for adduct-induced tumor initiation and progression.Several DNA repair mechanisms protect cells from the deleterious effects of DNA lesions. For example, bulky DNA adducts such as PAH adducts and the formamidopyrimidine adduct of aflatoxin are primarily repaired by nucleotide excision repair (17, 18), although some unstable B[a]P DE adducts might promote depurination and elicit the base excision repair (BER...

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Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Cited by 371 publications

References 32 publications

Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis

Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis

Simultaneous analysis of four stereoisomers of anti-benzo[a]pyrene diol epoxide–deoxyguanosine adducts in short oligodeoxynucleotides using reversed-phase high-performance liquid chromatography

Structure of DNA polymerase β with a benzo[ c ]phenanthrene diol epoxide-adducted template exhibits mutagenic features

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