Tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of fluorinated derivatives of benzo[a]pyrene and 3-methylcholanthrene

Cavalieri, Ercole L.; Rogan, Eleanor G.; Higginbotham, Sheila; Cremonesi, Paolo; Salmasi, Shahrokh

doi:10.1007/bf00390480

Cited by 22 publications

(26 citation statements)

References 19 publications

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“…For example, 6-fluorobenzo[ c ]phenanthrene (6-F-B c Ph) showed increased tumorigenicity as compared to benzo[ c ]phenanthrene (B c Ph), 8 whereas 6-fluorobenzo[ a ]pyrene (6-F-B a P) showed decreased tumorigenicity as compared to benzo[ a ]pyrene (B a P). 9 In the latter case this is attributed to fluorine-atom-induced conformational change in the metabolite. 9b Studies on the effect molecular distortion of PAHs can have on metabolic activation and DNA binding have been conducted using 1,4-difluorobenzo[ c ]phenanthrene as a model compound.…”

Section: Introductionmentioning

confidence: 99%

“…9 In the latter case this is attributed to fluorine-atom-induced conformational change in the metabolite. 9b Studies on the effect molecular distortion of PAHs can have on metabolic activation and DNA binding have been conducted using 1,4-difluorobenzo[ c ]phenanthrene as a model compound. 10 In order to better understand the structure-activity relationships on molecular-genetic level, availability of sufficient quantities of regiospecifically fluorinated PAHs is critical.…”

Section: Introductionmentioning

confidence: 99%

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Regiospecifically Fluorinated Polycyclic Aromatic Hydrocarbons via Julia–Kocienski Olefination and Oxidative Photocyclization. Effect of Fluorine Atom Substitution on Molecular Shape

et al. 2016

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A modular synthesis of regiospecifically fluorinated polycyclic aromatic hydrocarbons (PAHs) is described. 1,2-Diarylfluoroethenes, synthesized via Julia-Kocienski olefination (70–99% yields), were converted to isomeric 5- and 6-fluorobenzo[c]phenanthrene, 5-and 6-fluorochrysene, and 9- and 10-benzo[g]chrysene (66–83% yields) by oxidative photocyclization. Photocyclization to 6-fluorochrysene proceeded more slowly than conversion of 1-styrylnaphthalene to chrysene. Higher fluoroalkene dilution led to a more rapid cyclization. Therefore, photocyclizations were performed at higher dilutions. To evaluate the effect of fluorine atom on molecular shapes, X-ray data for 5- and 6-fluorobenzo[c]phenanthrene, 6-fluorochrysene, 9- and 10-fluorobenzo[g]chrysene, and unfluorinated chrysene as well as benzo[g]chrysene were obtained and compared. The fluorine atom caused a small deviation from planarity in the chrysene series, decreased nonplanarity in the benzo[c]phenanthrene derivatives, but its influence was most pronounced in the benzo[g]chrysene series. A remarkable flattening of the molecule was observed in 9-fluorobenzo[g]chrysene, where the short 2.055 Å interatomic distance between bay-region F-9 and H-8, downfield shift of H-8, and a 26.1 Hz coupling between F-9 and C-8 indicate a possible F-9··· H-8 hydrogen bond. Also, in 9-fluorobenzo[g]chrysene, stacking distance is short at 3.365 Å and there is an additional interaction between the C-11–H and C-10a of a nearby molecule that is almost perpendicular.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regiospecifically Fluorinated Polycyclic Aromatic Hydrocarbons via Julia–Kocienski Olefination and Oxidative Photocyclization. Effect of Fluorine Atom Substitution on Molecular Shape

et al. 2016

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“…6-Fluoro-BP is a weaker carcinogen than BP (26,39). The profile of stable adducts of 6-fluoro-BP formed in vitro after activation by rat liver microsomes resembles that of BP (23), but its depurinating adducts have not been analyzed.…”

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confidence: 99%

Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: the role of apurinic sites.

Chakravarti

Pelling

Cavalieri

et al. 1995

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

187

208

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Mouse skin tumors contain activated c-H-ras oncogenes, often caused by point mutations at codons 12 and 13 in exon 1 and codons 59 and 61 in exon 2. Mutagenesis by the noncoding apurinic sites can produce G -* T and A --T transversions by DNA misreplication with more frequent insertion of deoxyadenosine opposite the apurinic site. Papillomas were induced in mouse skin by several aromatic hydrocarbons, and mutations in the c-H-ras gene were determined to elucidate the relationship among DNA adducts, apurinic sites, and ras oncogene mutations. Dibenzo-[a,l pyrene (DB[a,l]P), DB [a,l]P-11,12-dihydrodiol, anti-DB[a,l]P-11,12-diol-13,14-epoxide, DB[a,l]P-8,9-dihydrodiol, 7,12-dimethylbenz [a] anthracene (DMBA), and 1,2,3,4-tetrahydro-DMBA consistently induced a CAA -> CTA mutation in codon 61 of the c-H-ras oncogene. Benzo[a]pyrene induced a GGC -* GTC mutation in codon 13 in 54% of tumors and a CAA -> CTA mutation in codon 61 in 15%. The pattern of mutations induced by each hydrocarbon correlated with its profile of DNA adducts. For example, both DB[a,l]P and DMBA primarily form DNA adducts at the N-3 and/or N-7 of deoxyadenosine that are lost from the DNA by depurination, generating apurinic sites. Thus, these results support the hypothesis that misreplication of unrepaired apurinic sites generated by loss of hydrocarbon-DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.The ras family of oncogenes includes the closely related H-, Kirsten-, and N-ras genes.

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“…In contrast, 6-methyl BP (6-CH 3 BP) ( Fig. 1) is mutagenic [5,6], teratogenic [7] and carcinogenic, although it is a weaker carcinogen than BP [8][9][10][11]. In addition, 6-CH 3 BP is produced by bioalkylation of BP with rat liver cytosol and S-adenosyl methionine, and therefore, has been suggested as a possible contributor in BP carcinogenesis [12,13].…”

Section: Introductionmentioning

confidence: 99%

SENCAR Mouse Skin Papillomas Induced by 6-Methylbenzo[a]pyrene Carry H-ras Codon 52 (CTALeu → CCAPro) and Codon 13 (GGCGly → GTCVal) Mutations

Chakravarti¹,

Mailander²,

Cavalieri³

et al. 2007

TODJ

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Organic smoke contains various methylated polycyclic aromatic hydrocarbon (PAH) carcinogens. Among these, 6-methylbenzo[a]pyrene (6-CH 3 BP) is a moderate carcinogen. In vitro, it can form both stable and depurinating adducts. Of these, only two depurinating adducts [BP-6-CH 2 -N7G and 6-CH 2 BP-(1&3)-N7G] have been detected in mouse skin. We examined seven 6-CH 3 BP-induced SENCAR mouse skin papillomas for the presence of oncogenic H-ras mutations. Two papillomas contained the codon 52 (CTA Leu CCA Pro ) and a third contained the codon 13 (GGC Gly GTC Val ) mutation. These results suggest that the H-ras codon 52 mutation is an oncogenic mutation.

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Tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of fluorinated derivatives of benzo[a]pyrene and 3-methylcholanthrene

Cited by 22 publications

References 19 publications

Regiospecifically Fluorinated Polycyclic Aromatic Hydrocarbons via Julia–Kocienski Olefination and Oxidative Photocyclization. Effect of Fluorine Atom Substitution on Molecular Shape

Regiospecifically Fluorinated Polycyclic Aromatic Hydrocarbons via Julia–Kocienski Olefination and Oxidative Photocyclization. Effect of Fluorine Atom Substitution on Molecular Shape

Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: the role of apurinic sites.

SENCAR Mouse Skin Papillomas Induced by 6-Methylbenzo[a]pyrene Carry H-ras Codon 52 (CTALeu → CCAPro) and Codon 13 (GGCGly → GTCVal) Mutations

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