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  1 / 20 MEDLINE  
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[PMID]:19187038
[Au] Autor:Hecht SS; Berg JZ; Hochalter JB
[Ad] Endereço:Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA. hecht002@umn.edu
[Ti] Título:Preferential glutathione conjugation of a reverse diol epoxide compared to a bay region diol epoxide of phenanthrene in human hepatocytes: relevance to molecular epidemiology studies of glutathione-s-transferase polymorphisms and cancer.
[So] Source:Chem Res Toxicol;22(3):426-32, 2009 Mar 16.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bay region diol epoxides are recognized ultimate carcinogens of polycyclic aromatic hydrocarbons (PAH), and in vitro studies have demonstrated that they can be detoxified by conjugation with glutathione, leading to the widely investigated hypothesis that individuals with low activity forms of glutathione-S-transferases are at higher risk of PAH induced cancer, a hypothesis that has found at most weak support in molecular epidemiology studies. A weakness in this hypothesis was that the mercapturic acids resulting from the conjugation of PAH bay region diol epoxides had never been identified in human urine. We recently analyzed smokers' urine for mercapturic acids derived from phenanthrene, the simplest PAH with a bay region. The only phenanthrene diol epoxide-derived mercapturic acid in smokers' urine was produced from the reverse diol epoxide, anti-phenanthrene-3,4-diol-1,2-epoxide (11), not the bay region diol epoxide, anti-phenanthrene-1,2-diol-3,4-epoxide (10), which does not support the hypothesis noted above. In this study, we extended these results by examining the conjugation of phenanthrene metabolites with glutathione in human hepatocytes. We identified the mercapturic acid N-acetyl-S-(r-4,t-2,3-trihydroxy-1,2,3,4-tetrahydro-c-1-phenanthryl)-L-cysteine (14a), (0.33-35.9 pmol/mL at 10 microM 8, 24 h incubation, N = 10) in all incubations with phenanthrene-3,4-diol (8) and the corresponding diol epoxide 11, but no mercapturic acids were detected in incubations with phenanthrene-1,2-diol (7), and only trace amounts were observed in incubations with the corresponding bay region diol epoxide 10. Taken together with our previous results, these studies clearly demonstrate that glutathione conjugation of a reverse diol epoxide of phenanthrene is favored over conjugation of a bay region diol epoxide. Since reverse diol epoxides of PAH are generally weakly or nonmutagenic/carcinogenic, these results, if generalizable to other PAH, do not support the widely held assumption that glutathione-S-transferases are important in the detoxification of PAH in humans.
[Mh] Termos MeSH primário: Glutationa Transferase/genética
Glutationa/metabolismo
Hepatócitos/metabolismo
Fenantrenos/metabolismo
[Mh] Termos MeSH secundário: Acetilcisteína/urina
Adulto
Idoso
Idoso de 80 Anos ou mais
Região de Baía de Hidrocarbonetos Aromáticos Policíclicos
Feminino
Seres Humanos
Masculino
Desintoxicação Metabólica Fase II
Meia-Idade
Neoplasias/genética
Fenantrenos/química
Fenantrenos/urina
Polimorfismo Genético
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Phenanthrenes); EC 2.5.1.18 (Glutathione Transferase); GAN16C9B8O (Glutathione); WYQ7N0BPYC (Acetylcysteine)
[Em] Mês de entrada:1011
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090204
[St] Status:MEDLINE
[do] DOI:10.1021/tx800315m


  2 / 20 MEDLINE  
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[PMID]:18848825
[Au] Autor:Mattsson A; Jernström B; Cotgreave IA; Bajak E
[Ad] Endereço:Institute of Environmental Medicine, Division of Biochemical Toxicology, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden.
[Ti] Título:H2AX phosphorylation in A549 cells induced by the bulky and stable DNA adducts of benzo[a]pyrene and dibenzo[a,l]pyrene diol epoxides.
[So] Source:Chem Biol Interact;177(1):40-7, 2009 Jan 15.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Early events in the cellular response to DNA damage, such as double strand breaks, rely on lesion recognition and activation of proteins involved in maintenance of genomic stability. One important component of this process is the phosphorylation of the histone variant H2AX. To investigate factors explaining the variation in carcinogenic potency between different categories of polycyclic aromatic hydrocarbons (PAHs), we have studied the phosphorylation of H2AX (H2AXgamma). A549 cells were exposed to benzo[a]pyrene diol epoxide [(+)-anti-BPDE] (a bay-region PAH) and dibenzo[a,l]pyrene diol epoxide [(-)-anti-DBPDE] (a fjord-region PAH) and H2AXgamma was studied using immunocytochemistry and Western blot. Hydrogen peroxide (H(2)O(2)) was used to induce oxidative DNA damage and strand breaks. As showed with single cell gel electrophoresis, neither of the diol epoxides resulted in DNA strand breaks relative to H(2)O(2). Visualisation of H2AXgamma formation demonstrated that the proportion of cells exhibiting H2AXgamma staining at 1h differed between BPDE, 40% followed by a decline, and DBPDE, <10% followed by an increase. With H(2)O(2) treatment, almost all cells demonstrated H2AXgamma at 1h. Western blot analysis of the H2AXgamma formation also showed concentration and time-dependent response patterns. The kinetics of H2AXgamma formation correlated with the previously observed kinetics of elimination of BPDE and DBPDE adducts. Thus, the extent of H2AXgamma formation and persistence was related to both the number of adducts and their structural features.
[Mh] Termos MeSH primário: 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/farmacologia
Benzo(a)pireno/farmacologia
Benzopirenos/farmacologia
Adutos de DNA/farmacologia
Compostos de Epóxi/farmacologia
Histonas/metabolismo
[Mh] Termos MeSH secundário: Região de Baía de Hidrocarbonetos Aromáticos Policíclicos
Western Blotting
Linhagem Celular Tumoral
Ensaio Cometa
Dano ao DNA
Fragmentação do DNA/efeitos dos fármacos
Seres Humanos
Imuno-Histoquímica
Fosforilação/efeitos dos fármacos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzopyrenes); 0 (DNA Adducts); 0 (Epoxy Compounds); 0 (H2AFX protein, human); 0 (Histones); 0 (dibenzo(a,l)pyrene diol epoxide); 153857-28-4 (11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo(a,l)pyrene); 3417WMA06D (Benzo(a)pyrene); 55097-80-8 (7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide)
[Em] Mês de entrada:0901
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:081014
[St] Status:MEDLINE
[do] DOI:10.1016/j.cbi.2008.09.015


  3 / 20 MEDLINE  
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[PMID]:12926280
[Au] Autor:Okazaki T; Laali KK; Zajc B; Lakshman MK; Kumar S; Baird WM; Dashwood WM
[Ad] Endereço:Department of Chemistry, Kent State University, Kent, OH 44242, USA.
[Ti] Título:Stable ion study of benzo[a]pyrene (BaP) derivatives: 7,8-dihydro-BaP, 9,10-dihydro-BaP and its 6-halo derivatives, 1- and 3-methoxy-9,10-dihydro-BaP-7(8H)-one, as well as the proximate carcinogen BaP 7,8-dihydrodiol and its dibenzoate, combined with a comparative DNA binding study of regioisomeric (1-, 4-, 2-) pyrenylcarbinols.
[So] Source:Org Biomol Chem;1(9):1509-16, 2003 May 07.
[Is] ISSN:1477-0520
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A stable ion study of a series of BaP derivatives is reported. 7,8-Dihydro-BaP 1 gives a persistent bay-region benzyliclike carbocation which shows extensive charge delocalization into the pyrene moiety. In contrast, a "benzylic" carbocation can not be generated from 9,10-dihydro-BaP 2. Introduction of bulky substituents at peri C-6 of 9,10-dihydro-BaP (as in 4 and 5) prevents side reactions (dimerization) to the extent that the initially formed carbocation undergoes rearrangement to generate the corresponding bay-region "benzylic" carbocation as a persistent species. Introduction of methoxy substituents into the 1- or 3-positions of 9,10-dihydro-BaP-7(8H)-one (6,7) increases its electrophilic reactivity to the extent that stable carboxonium-arenium dications are produced in FSO3H-SO2ClF. A detailed NMR study (at 500 MHz) of the resulting mono- and dications is reported, and charge delocalization mode (as well as conformational aspects) are addressed. Other oxidized derivatives of BaP such as the 7,8-dihydrodiol 9 and the 7,8-dihydrodibenzoate 8 are not suitable models for stable ion study because of competing O-protonation (and elimination). Energies for various possible arenium ions and regioisomeric "benzylic" cations were computed by the DFT method at the B3LYP/6-31G(d)//B3LYP/6-31G(d) level or by AM1 for comparison with the experimental results. These findings provide further evidence in support of the stability sequence: 1-pyrenyl > 4-pyrenyl > 2-pyrenyl in alpha-pyrene-substituted carbocations as models for the intermediates arising from BaP-epoxide ring opening. In an effort to provide a parallel, a series of alpha-pyrenylcarbinols were subjected to a DNA binding study using human MCF-7 cells. The results/trends are discussed and compared with the stable ion data.
[Mh] Termos MeSH primário: Benzo(a)pireno/análogos & derivados
Benzo(a)pireno/metabolismo
DNA/metabolismo
[Mh] Termos MeSH secundário: Animais
Região de Baía de Hidrocarbonetos Aromáticos Policíclicos
Carcinógenos/química
Carcinógenos/metabolismo
Cátions
Bovinos
Adutos de DNA/química
Compostos de Epóxi/química
Seres Humanos
Substâncias Intercalantes/química
Substâncias Intercalantes/metabolismo
Metanol/química
Metanol/metabolismo
Ressonância Magnética Nuclear Biomolecular
Estereoisomerismo
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Carcinogens); 0 (Cations); 0 (DNA Adducts); 0 (Epoxy Compounds); 0 (Intercalating Agents); 3417WMA06D (Benzo(a)pyrene); 9007-49-2 (DNA); Y4S76JWI15 (Methanol)
[Em] Mês de entrada:0401
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:030821
[St] Status:MEDLINE


  4 / 20 MEDLINE  
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[PMID]:11765016
[Au] Autor:Conney AH; Chang RL; Cui XX; Schiltz M; Yagi H; Jerina DM; Wei SJ
[Ad] Endereço:Department of Chemical Biology, College of Pharmacy, Rutgers, the State University of New Jersey, Piscataway 08854-8020, USA.
[Ti] Título:Dose-dependent differences in the profile of mutations induced by carcinogenic (R,S,S,R) bay- and fjord-region diol epoxides of polycyclic aromatic hydrocarbons.
[So] Source:Adv Exp Med Biol;500:697-707, 2001.
[Is] ISSN:0065-2598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chinese hamster V79 cells were exposed to a high or low concentration of the highly carcinogenic (R,S,S,R) or the less active (S,R,R,S) bay- or fjord-region diol epoxides of benzo[a]pyrene, benzo[c]phenanthrene or dibenz[c,h]acridine. Independent 8-azaguanine-resistant clones were isolated, and base substitutions at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) locus were determined. For the three (R,S,S,R) diol epoxides studied, the proportion of mutations at AT base pairs increased as the concentration of diol epoxide decreased. Concentration-dependent differences in the mutational profile were not observed, however, for the three (S,R,R,S) diol epoxides. In studies, with V-H1 cells (a DNA repair deficient variant of V79 cells), a concentration-dependent difference in the profile of mutations for the (R,S,S,R) diol epoxide of benzo[a]pyrene was not observed. These results suggest that concentration-dependent differences in the mutational profile are dependent on an intact DNA repair system. In additional studies, we initiated mouse skin with a high or low dose of benzo[a]pyrene and promoted the mice for 26 weeks with 12-O-tetradecanoylphorbol-13-acetate. Papillomas were examined for mutations in the c-Ha-ras proto-oncogene. Dose-dependent differences in the profile of c-Ha-ras mutations in the tumors were observed. In summary, (i) dose-dependent differences in mutational profiles at the hprt locus were observed in Chinese hamster V79 cells treated with several highly mutagenic and carcinogenic (R,S,S,R) bay- or fjord-region diol epoxides but not with their less active (S,R,R,S) diol epoxide enantiomers, (ii) a dose-dependent difference in the mutational profile was not observed for the (R,S,S,R) diol epoxide of benzo[a]pyrene in a DNA-repair defective V79 cell line, and (iii) a dose-dependent difference in the mutational profile in the c-Ha-ras proto-oncogene was observed in tumors from mice treated with a high or low dose of benzo[a]pyrene.
[Mh] Termos MeSH primário: Acridinas/efeitos adversos
Carcinógenos/efeitos adversos
Hipoxantina Fosforribosiltransferase/genética
Fenantrenos/efeitos adversos
[Mh] Termos MeSH secundário: Acridinas/farmacologia
Substituição de Aminoácidos
Animais
Sequência de Bases
Região de Baía de Hidrocarbonetos Aromáticos Policíclicos
Benzo(a)pireno/efeitos adversos
Benzo(a)pireno/farmacologia
Carcinógenos/farmacologia
Relação Dose-Resposta a Droga
Compostos de Epóxi
Genes ras
Seres Humanos
Dados de Sequência Molecular
Mutagênese
Fenantrenos/farmacologia
Hidrocarbonetos Aromáticos Policíclicos/efeitos adversos
Hidrocarbonetos Aromáticos Policíclicos/farmacologia
Neoplasias Cutâneas/tratamento farmacológico
Neoplasias Cutâneas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.; REVIEW
[Nm] Nome de substância:
0 (Acridines); 0 (Carcinogens); 0 (Epoxy Compounds); 0 (Phenanthrenes); 0 (Polycyclic Aromatic Hydrocarbons); 224-53-3 (dibenz(c,h)acridine); 3417WMA06D (Benzo(a)pyrene); EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase); H22XVR3V8A (benzo(c)phenanthrene)
[Em] Mês de entrada:0207
[Cu] Atualização por classe:161124
[Lr] Data última revisão:
161124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:020105
[St] Status:MEDLINE


  5 / 20 MEDLINE  
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[PMID]:11389588
[Au] Autor:Li Z; Tamura PJ; Wilkinson AS; Harris CM; Harris TM; Stone MP
[Ad] Endereço:Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37235, USA.
[Ti] Título:Intercalation of the (1R,2S,3R,4S)-N6-[1-(1,2,3,4-tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2'-deoxyadenosyl adduct in the N-ras codon 61 sequence: DNA sequence effects.
[So] Source:Biochemistry;40(23):6743-55, 2001 Jun 12.
[Is] ISSN:0006-2960
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The structure of the bay region (1R,2S,3R,4S)-N6-[1-(1,2,3,4-tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2'-deoxyadenosyl adduct at X(7) of 5'-d(CGGACAXGAAG)-3'.5'-d(CTTCTTGTCCG)-3', incorporating codons 60, 61 (underlined), and 62 of the human N-ras protooncogene, was determined by NMR. This was the bay region benz[a]anthracene RSRS (61,3) adduct. The BA moiety intercalated above the 5'-face of the modified base pair. NOE connectivities between imino protons were disrupted at T16 and T17. Large chemical shifts at the lesion site were consistent with ring current shielding arising from the BA moiety. A large chemical shift dispersion was observed for the BA aromatic protons. An increased rise of 8.17 A was observed between base pairs A6 x T17 and X7 x T(16). The PAH moiety stacked with the purine ring of A6, the 5'-neighbor nucleotide. This resulted in buckling of the 5'-neighbor A6 x T17 base pair, evidenced by exchange broadening for the T17 imino resonance. It also interrupted sequential NOE connectivities between nucleotides C5 and A6. The A6 deoxyribose ring showed an increased percentage of the C3'-endo conformation. This differed from the bay region BA RSRS (61,2) adduct, in which the lesion was located at position X6 [Li, Z., Mao, H., Kim, H.-Y., Tamura, P. J., Harris, C. M., Harris, T. M., and Stone, M. P. (1999) Biochemistry 38, 2969-2981], but was similar to the benzo[a]pyrene BP SRSR (61,3) adduct [Zegar I. S., Chary, P., Jabil, R. J., Tamura, P. J., Johansen, T. N., Lloyd, R. S., Harris, C. M., Harris, T. M., and Stone, M. P. (1998) Biochemistry 37, 16516-16528]. The altered sugar pseudorotation at A6 appears to be common to both bay region BA RSRS (61,3) and BP SRSR (61,3) adducts. It could not be discerned if the C3'-endo conformation at A6 in the BA RSRS (61,3) adduct altered base pairing geometry at X7 x T16, as compared to the C2'-endo conformation. The structural studies suggest that the mutational spectrum of this adduct may be more complex than that of the BA RSRS (61,2) adduct.
[Mh] Termos MeSH primário: Benzo(a)Antracenos/química
Códon/química
Adutos de DNA/química
Genes ras/genética
Substâncias Intercalantes/química
Mutagênese Sítio-Dirigida
[Mh] Termos MeSH secundário: Adenina/química
Pareamento de Bases
Região de Baía de Hidrocarbonetos Aromáticos Policíclicos
Configuração de Carboidratos
Desoxirribose/química
Seres Humanos
Ressonância Magnética Nuclear Biomolecular
Oligodesoxirribonucleotídeos/química
Prótons
Soluções
Estereoisomerismo
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Benz(a)Anthracenes); 0 (Codon); 0 (DNA Adducts); 0 (Intercalating Agents); 0 (Oligodeoxyribonucleotides); 0 (Protons); 0 (Solutions); 533-67-5 (Deoxyribose); 60839-18-1 (benzanthracene-3,4-dihydrodiol); 64551-89-9 (3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz(a)anthracene); JAC85A2161 (Adenine)
[Em] Mês de entrada:0108
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:010608
[St] Status:MEDLINE


  6 / 20 MEDLINE  
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[PMID]:11377239
[Au] Autor:Catterall FS; Coombs MM; Ioannides C; Sepiol JJ; Wilson J
[Ad] Endereço:Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford, GU2 7XH, Surrey, UK.
[Ti] Título:Mutagenicity of bay-region amino-substituted cyclopenta[a]phenanthrenes and 2- and 5-aminochrysene.
[So] Source:Mutat Res;492(1-2):7-11, 2001 May 31.
[Is] ISSN:0027-5107
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The relative mutagenic potentials of 11-amino-16,17-dihydro-15H-cyclopenta[a]phenanthrene, its 17-keto derivative, and 2- and 5-aminochrysene have been compared in Salmonella typhimurium TA98 and TA100 in the presence of a postmitochondrial liver preparation from Aroclor 1254 induced rats. The 11-amino hydrocarbon is a very weak mutagen (0.27 revertants/nmol), whereas the 11-amino-17-ketone is much more active (129 revertants/nmol). 2-Aminochrysene is the most mutagenic arylamine ( approximately 500 revertants/nmol) among these compounds, but its 5-amino isomer is much less active (0.9 revertants/nmol). Possible reasons for these marked differences are suggested. Use of TA98 with over-expressing O-acetyltransferase (YG 1024) and deficient in this enzyme (TA98/l,8-DNP(6)) with the 11-amino-17-ketone and with 5-aminochrysene clearly indicates the importance of this enzyme in their bioactivation, implying oxidation of the amino group to the hydroxylamine in both these compounds.
[Mh] Termos MeSH primário: Androstenos/toxicidade
Crisenos/toxicidade
Mutagênicos/toxicidade
[Mh] Termos MeSH secundário: Animais
Região de Baía de Hidrocarbonetos Aromáticos Policíclicos
Masculino
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
Testes de Mutagenicidade
Ratos
Ratos Wistar
Salmonella typhimurium/efeitos dos fármacos
Salmonella typhimurium/genética
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (11-amino-16,17-dihydro-15H-cyclopenta(a)phenanthrene); 0 (Androstenes); 0 (Chrysenes); 0 (Mutagens); I56L81BL2L (6-chrysenamine); S00XF35AE0 (2-aminochrysene)
[Em] Mês de entrada:0108
[Cu] Atualização por classe:121115
[Lr] Data última revisão:
121115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:010530
[St] Status:MEDLINE


  7 / 20 MEDLINE  
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[PMID]:11112546
[Au] Autor:Yang Y; Griffiths WJ; Nordling M; Nygren J; Möller L; Bergman J; Liepinsh E; Otting G; Gustafsson JA; Rafter J; Sjövall J
[Ad] Endereço:Department of Medical Biochemistry & Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
[Ti] Título:Ring opening of benzo[a]pyrene in the germ-free rat is a novel pathway for formation of potentially genotoxic metabolites.
[So] Source:Biochemistry;39(50):15585-91, 2000 Dec 19.
[Is] ISSN:0006-2960
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The metabolism of benzo[a]pyrene (BP) is known to lead to a large number of oxygenated compounds, some of which can bind covalently to DNA. We have studied the integrated metabolism of BP in vivo in germ-free rats given (14)C-labeled BP. Urinary metabolites were separated into groups according to acidity using lipophilic ion exchangers. The groups were analyzed by mass spectrometry and were further fractionated by high-performance liquid chromatography. The fraction of urinary metabolites previously shown to contain N-acetylcysteine and glucuronic acid conjugates was found to contain derivatives of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid as major components. These compounds, which were identified by mass spectrometry and NMR, accounted for about 30% of the total metabolites in urine, demonstrating that, surprisingly, ring opening is a major pathway for metabolism of BP in the germ-free rat. The dicarboxylic acid may be excreted in urine as an ester glucuronide. By using the single cell gel electrophoresis or COMET assay, we were able to demonstrate that the anhydride of 7-oxo-benz[d]anthracene-3, 4-dicarboxylic acid was an efficient inducer of DNA damage. Taken together, these results indicate that the novel ring opening metabolic pathway may provide alternative mechanisms for the toxicity of BP.
[Mh] Termos MeSH primário: Benzo(a)pireno/química
Benzo(a)pireno/toxicidade
[Mh] Termos MeSH secundário: Animais
Região de Baía de Hidrocarbonetos Aromáticos Policíclicos
Benzo(a)pireno/metabolismo
Dano ao DNA
Vida Livre de Germes
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
3417WMA06D (Benzo(a)pyrene)
[Em] Mês de entrada:0101
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:001212
[St] Status:MEDLINE


  8 / 20 MEDLINE  
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[PMID]:11062160
[Au] Autor:Chang RL; Wood AW; Kumar S; Lehr RE; Shirai N; Jerina DM; Conney AH
[Ad] Endereço:Laboratory for Cancer Research, Rutgers, The State University of New Jersey, College of Pharmacy, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
[Ti] Título:Tumorigenicity of four optically active bay-region 3,4-diol 1, 2-epoxides and other derivatives of the nitrogen heterocycle dibenz[c,h]acridine on mouse skin and in newborn mice.
[So] Source:Carcinogenesis;21(11):1997-2003, 2000 Nov.
[Is] ISSN:0143-3334
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The nitrogen heterocycle dibenz[c,h]acridine (DB[c,h]ACR) and the enantiomers of the diastereomeric pair of bay-region 3,4-diol 1, 2-epoxides as well as other bay-region epoxides and dihydrodiol derivatives of this hydrocarbon have been evaluated for tumorigenicity on mouse skin and in the newborn mouse. On mouse skin, a single topical application of 50 or 200 nmol of compound was followed 10 days later by twice-weekly applications of the tumor promoter 12-O:-tetradecanoylphorbol-13-acetate for 20 weeks. DB[c, h]ACR and the four optically pure, bay-region 3,4-diol-1,2-epoxide isomers all had significant tumor- initiating activity. The isomer with (1R,2S,3S,4R) absolute configuration [(+)-DE-2] was the most active diol epoxide isomer. The (-)-(3R,4R)-dihydrodiol of DB[c, h]ACR, the expected metabolic precursor of the bay-region (+)-DE-2, was 4- to 6-fold more tumorigenic than its corresponding (+)-enantiomer. In tumorigenicity studies in newborn mice, a total dose of 70-175 nmol of DB[c,h]ACR or one of its derivatives was injected i.p. on days 1, 8 and 15 of life, and tumorigenic activity was determined when the mice were 36-39 weeks old. DB[c,h]ACR produced a significant number of pulmonary tumors and also produced hepatic tumors in male mice. Of the four optically active bay-region diol epoxides, only (+)-DE-2 and (+)-DE-1 with (1R,2S,3S,4R) and (1S, 2R,3S,4R) absolute configuration, respectively, produced a significant tumor incidence. At an equivalent dose, the (+)-DE-2 isomer produced several-fold more pulmonary tumors and hepatic tumors than the (+)-DE-1 isomer. The (-)-(3R,4R)-dihydrodiol, metabolic precursor of the bay-region (+)-DE-2, was strongly active and induced an equal number of pulmonary and hepatic tumors as did DB[c,h]ACR. The (+)-(3S,4S) dihydrodiol was less active. The bay-region (+)-(1R,2S)-epoxide of 1,2,3,4-tetrahydro DB[c,h]ACR was strongly tumorigenic in newborn mice whereas its (-)-(1S, 2R)-enantiomer was inactive. This contrasts with the data on mouse skin where both enantiomers had substantial tumorigenic activity. In summary, the bay-region (+)-(1R,2S,3S,4R)-3,4-diol 1,2-epoxide of DB[c,h]ACR was the most tumorigenic of the four optically active bay-region diol epoxides of DB[c,h]ACR on mouse skin and in the newborn mouse. These results with a nitrogen heterocycle are similar to earlier data indicating high tumorigenic activity for the R,S,S,R bay-region diol epoxides of several carbocyclic polycyclic aromatic hydrocarbons.
[Mh] Termos MeSH primário: Acridinas/toxicidade
Carcinógenos/toxicidade
Neoplasias Cutâneas/induzido quimicamente
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Região de Baía de Hidrocarbonetos Aromáticos Policíclicos
Compostos de Epóxi/toxicidade
Feminino
Neoplasias Hepáticas Experimentais/induzido quimicamente
Neoplasias Pulmonares/induzido quimicamente
Masculino
Camundongos
Gravidez
Pele/efeitos dos fármacos
Estereoisomerismo
Relação Estrutura-Atividade
Acetato de Tetradecanoilforbol/toxicidade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Acridines); 0 (Carcinogens); 0 (Epoxy Compounds); 088X9K64S8 (dibenzacridine); NI40JAQ945 (Tetradecanoylphorbol Acetate)
[Em] Mês de entrada:0012
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:001104
[St] Status:MEDLINE


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[PMID]:10995261
[Au] Autor:Vepachedu SR; Ya N; Yagi H; Sayer JM; Jerina DM
[Ad] Endereço:Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, Maryland 20892-0820, USA.
[Ti] Título:Marked differences in base selectivity between DNA and the free nucleotides upon adduct formation from Bay- and Fjord-region diol epoxides.
[So] Source:Chem Res Toxicol;13(9):883-90, 2000 Sep.
[Is] ISSN:0893-228X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Distributions of adducts formed from each of the four optically active isomers of 3,4-dihydroxy-1,2-epoxy-1,2,3, 4-tetrahydrobenzo[c]phenanthrene and of 7,8-dihydroxy-9,10-epoxy-7,8, 9,10- tetrahydrobenzo[a]pyrene (BcPh and BaP diol epoxides) on reaction with an equimolar mixture of deoxyadenosine and deoxyguanosine 5'-monophosphates were compared with the known adduct distributions from these diol epoxides (DEs) upon reaction with calf thymus DNA in vitro. In the presence of an equimolar (100 mM total) mixture of dAMP and dGMP, the efficiency of formation of all types of adducts relative to tetraols is comparable for both the BaP ( approximately 40-60%) and BcPh ( approximately 30-40%) diol epoxides. This is in contrast to the partitioning between tetraols and adducts observed with DNA, where the BcPh DEs form adducts much more efficiently than the BaP DEs. Preference for trans versus cis ring opening by the exocyclic amino groups of the free nucleotides in the dAMP/dGMP mixture is greater for the DE diastereomer in which the benzylic hydroxyl group and the epoxide oxygen are trans (DE-2). This is qualitatively similar to the preferences for trans versus cis adduct formation on reaction of these isomers with DNA, as well as trans versus cis tetraol formation on their acid hydrolysis. For the BcPh DE isomers, competitive reaction between dGMP and dAMP gives 40-62% of the total exocyclic amino group adducts as dA adducts. A similar distribution of dG versus dA adducts had previously been observed on reaction of the BcPh DEs with DNA, except in the case of (+)-3(R),4(S)-dihydroxy-1(R),2(S)-epoxy-1,2,3, 4-tetrahydrobenzo[c]phenanthrene, which gives approximately 85% dA adducts on reaction with DNA. With the BaP DEs, 60-77% of the exocyclic amino group adducts formed upon competitive reaction with the free nucleotides are derived from dGMP. The observed dG selectivity of these BaP DEs is much smaller with the nucleotide mixture than it is with DNA, leading to the conclusion that DNA structure has a much larger modifying effect on the base selectivity of the BaP relative to the BcPh DEs.
[Mh] Termos MeSH primário: Região de Baía de Hidrocarbonetos Aromáticos Policíclicos
Adutos de DNA/química
DNA/química
Nucleotídeos de Desoxiadenina/química
Nucleotídeos de Desoxiguanina/química
Compostos de Epóxi/química
[Mh] Termos MeSH secundário: Animais
Benzo(a)pireno/química
Bovinos
Fenantrenos/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA Adducts); 0 (Deoxyadenine Nucleotides); 0 (Deoxyguanine Nucleotides); 0 (Epoxy Compounds); 0 (Phenanthrenes); 3417WMA06D (Benzo(a)pyrene); 9007-49-2 (DNA); H22XVR3V8A (benzo(c)phenanthrene)
[Em] Mês de entrada:0011
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:000920
[St] Status:MEDLINE


  10 / 20 MEDLINE  
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[PMID]:10649961
[Au] Autor:Melendez-Colon VJ; Luch A; Seidel A; Baird WM
[Ad] Endereço:Department of Environmental and Molecular Toxicology and Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331, USA.
[Ti] Título:Formation of stable DNA adducts and apurinic sites upon metabolic activation of bay and fjord region polycyclic aromatic hydrocarbons in human cell cultures.
[So] Source:Chem Res Toxicol;13(1):10-7, 2000 Jan.
[Is] ISSN:0893-228X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Carcinogenic polycyclic aromatic hydrocarbons (PAH), such as benzo[a]pyrene (B[a]P), 7,12-dimethylbenz[a]anthracene (DMBA), and dibenzo[a,l]pyrene (DB[a,l]P), are metabolically activated to electrophilically reactive bay or fjord region diol epoxides that bind to the exocyclic amino groups of purine bases in DNA to form stable adducts. In addition, it has been reported that these PAH can be enzymatically oxidized to yield radical cations that form apurinic (AP) sites in DNA via depurinating adducts. The formation of stable adducts and AP sites in DNA of human cells exposed to PAH was examined in cytochrome P450 (P450)-expressing mammary carcinoma MCF-7 cells and in leukemia HL-60 cells, which display a high peroxidase but no P450-mediated activity, after exposure to these PAH. Stable DNA adducts were assessed by (33)P-postlabeling/HPLC analysis, and the induction of AP sites in DNA was analyzed by an aldehyde reactive probe (ARP) and a slot blot method. After exposure for 4 h, the levels of stable DNA adducts were comparable in MCF-7 cells treated with B[a]P and DMBA, but significantly lower than those observed in MCF-7 cells treated with the stronger carcinogen DB[a,l]P. While the levels of stable adducts increased more than 10-fold (B[a]P and DMBA) or 100-fold (DB[a,l]P) after exposure for 24 h, the levels of AP sites remained low after both treatment periods. Thus, the levels of stable adducts were approximately 5-fold higher than the levels of AP sites after treatment with B[a]P or DMBA and more than 100-fold higher in cells exposed to DB[a,l]P for 24 h. None of these carcinogenic PAH formed detectable levels of stable DNA adducts or AP sites in HL-60 cells. The results demonstrate that metabolic activation of B[a]P, DMBA, and DB[a,l]P is catalyzed by P450 enzymes leading to diol epoxides that form predominantly stable DNA adducts but only low levels of AP sites.
[Mh] Termos MeSH primário: Ácido Apurínico/metabolismo
Carcinógenos/farmacocinética
Adutos de DNA/biossíntese
DNA de Neoplasias/efeitos dos fármacos
Hidrocarbonetos Aromáticos Policíclicos/farmacocinética
[Mh] Termos MeSH secundário: 9,10-Dimetil-1,2-benzantraceno/química
9,10-Dimetil-1,2-benzantraceno/metabolismo
9,10-Dimetil-1,2-benzantraceno/farmacocinética
Animais
Região de Baía de Hidrocarbonetos Aromáticos Policíclicos
Benzo(a)pireno/química
Benzo(a)pireno/metabolismo
Benzo(a)pireno/farmacocinética
Benzopirenos/química
Benzopirenos/metabolismo
Benzopirenos/farmacocinética
Biotransformação
Carcinógenos/química
Carcinógenos/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
DNA de Neoplasias/metabolismo
Relação Dose-Resposta a Droga
Células HL-60
Seres Humanos
Peroxidases/metabolismo
Hidrocarbonetos Aromáticos Policíclicos/química
Hidrocarbonetos Aromáticos Policíclicos/metabolismo
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Benzopyrenes); 0 (Carcinogens); 0 (DNA Adducts); 0 (DNA, Neoplasm); 0 (Polycyclic Aromatic Hydrocarbons); 11002-22-5 (Apurinic Acid); 3417WMA06D (Benzo(a)pyrene); 57-97-6 (9,10-Dimethyl-1,2-benzanthracene); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.11.1.- (Peroxidases); G3X629VE4A (dibenzo(a,l)pyrene)
[Em] Mês de entrada:0003
[Cu] Atualização por classe:161124
[Lr] Data última revisão:
161124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:000129
[St] Status:MEDLINE



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