P-32-postlabeling analysis of lipophilic DNA adducts resulting from interaction with (+/-)-3-hydroxy-trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene

Citation
Jm. Arif et al., P-32-postlabeling analysis of lipophilic DNA adducts resulting from interaction with (+/-)-3-hydroxy-trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, CHEM-BIO IN, 118(2), 1999, pp. 87-97
Citations number
18
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
CHEMICO-BIOLOGICAL INTERACTIONS
ISSN journal
0009-2797 → ACNP
Volume
118
Issue
2
Year of publication
1999
Pages
87 - 97
Database
ISI
SICI code
0009-2797(19990401)118:2<87:PAOLDA>2.0.ZU;2-S
Abstract
Bay-region diol epoxides are considered the putative ultimate carcinogens o f polynuclear aromatic hydrocarbons. However, the results of studies on tum origenesis and DNA binding of benzo[a]pyrene (BP) and its bay-region diol e poxide, (+)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a] pyrene [(+)-anti-BPDE] suggest that, in addition to anti-BPDE, other reacti ve metabolite(s) of BP may also be involved in BP-induced carcinogenesis. R ecent studies have demonstrated that 3-hydroxy-trans-7,8-dihydroxy-anti-9,1 0-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPTE) is another highly rea ctive metabolite of BP. In order to identify syn- and anti-BPTE-derived DNA adducts and their base selectivity, we synthesized both compounds by two d ifferent methods and reacted in vitro with calf thymus DNA and individual n ucleotides. The resultant adducts were analyzed by nuclease pi-enhanced P-3 2-postlabeling. Anti-BPTE produced three major and several minor adducts wi th DNA; dAp and dGp were the preferred substrates, while dCp and dTp were t he least reactive. In contrast, syn-BPTE produced two major adducts each wi th DNA and dGp; dAp generated only one adduct. Co-chromatography of anti-BP TE-derived DNA adducts with those of mononucleotide adducts revealed that t he major adducts in DNA were guanine derived. Further, co-chromatographic r esults revealed that the anti-BPTE-DNA adducts were distinctly different fr om that of anti-BPDE-DNA adducts. These observations indicate that both syn - and anti-BPTE can react with DNA bases and these DNA adducts may also con tribute to BP-induced carcinogenesis. (C) 1999 Elsevier Science Ireland Ltd . All rights reserved.