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Titolo:
trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tetrahydrodibenz[a,j]acridine involvement in dibenz[a,j]acridine DNA adduct formation in mouse skin consistent with Ha-ras mutation patterns in tumors
Autore:
Xue, WL; Schneider, J; Mitchell, K; Jaeger, M; Nanayakkara, V; Talaska, G; Warshawsky, D;
Indirizzi:
Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA Univ Cincinnati Cincinnati OH USA 45267 nm Hlth, Cincinnati, OH 45267 USA
Titolo Testata:
CHEMICAL RESEARCH IN TOXICOLOGY
fascicolo: 7, volume: 14, anno: 2001,
pagine: 871 - 878
SICI:
0893-228X(200107)14:7<871:TI>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
POLYCYCLIC AROMATIC-HYDROCARBONS; METABOLIC-ACTIVATION; DIHYDRODIOL EPOXIDE; ONCOGENE MUTATIONS; LIVER-MICROSOMES; BINDING; MICE; IDENTIFICATION; 7H-DIBENZOCARBAZOLE; CARCINOGENICITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Warshawsky, D Univ Cincinnati, Med Ctr, Dept Environm Hlth, POB 670056, Cincinnati, OH 45267 USA Univ Cincinnati POB 670056 Cincinnati OH USA 45267 45267 USA
Citazione:
W.L. Xue et al., "trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tetrahydrodibenz[a,j]acridine involvement in dibenz[a,j]acridine DNA adduct formation in mouse skin consistent with Ha-ras mutation patterns in tumors", CHEM RES T, 14(7), 2001, pp. 871-878

Abstract

Dibenz[a,j]acridine (DBA), is a N-heteropolycyclic aromatic environmental carcinogen found in complex combustion mixtures. The major route of DBA metabolic activation is reportedly through the trans-3,4-dihydroxy-3,4-dihydroDBA (DBA-3,4-DHD). The present studies were undertaken to determine the role of trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tetrahydroDBA (DBADE) in DBA activation pathway(s), the DNA bases involved in the binding of DBA to DNA, and whether the adducts produced are consistent with the mutation pattern in the Ha-ras gene. DBA (300 mug) or 50 mug synthesized (+/-)-DBADE was applied to the back of female Hsd:ICR(Br) mice. The mice were sacrificed 48 h later, and skin DNA was isolated, hydrolyzed, and analyzed with P-32-postlabeling. Of the four adducts produced in vivo, adduct 1 was the major adduct for DBA (> 50%) and adduct 2 was the major adduct for DBADE (89%). Afterthe reaction of (+/-)-DBADE with purine nucleotides or calf thymus (CT) DNA in vitro, 100% of the DBADE-2 ' -dAMP adducts and 94% of DBADE-CT DNA adducts were chromatographically identical on TLC with adduct 2 and 86% of theDBADE-2 ' -dGMP adducts were chromatographically consistent with adduct 1 by 32P-postlabeling. Papillomas were induced on the backs of mice by a single application of 0.2 mu mol of DBA followed by twice-weekly application of12-o-tetra-decanoylphorbol-13-acetate (TPA, 2 mug) for 24-26 weeks. Skin carcinomas were induced by twice weekly applications of DBA (0.1 mu mol) on the backs of mice. A to T and G to T transversions were found in codons 12,13, and 61 of the Ha-ras gene in the treated mouse skin carcinoma and papilloma DNA, The mutational spectra in the Ha-ras gene are consistent with the DNA binding of DBA to dG or dA in vivo. Thus, this research has indicatedthat DBADE plays an important role in DBA metabolic activation and DNA binding in mouse skin, and an alternative pathway through a bis-dihydrodiol-epoxide of DBA may also be involved.

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Documento generato il 06/04/20 alle ore 08:09:11