title: DNA adducts and carcinogenicity of nitro-polycyclic aromatic hydrocarbons.
abstract: We have been interested in the structure-activity relationships of nitro-polycyclic aromatic hydrocarbons (nitro-PAHs), and have focused on the correlation of structural and electronic features with biological activities, including mutagenicity and tumorigenicity. In our studies, we have emphasized 1-, 2-, 3-, and 6-nitrobenzo[a]pyrenes (nitro-B[a]Ps) and related compounds, all of which are derived from the potent carcinogen benzo[a]pyrene. While 1-, 2-, and 3-nitro-B[a]P are potent mutagens in Salmonella, 6-nitro-B[a]P is a weak mutagen. In vitro metabolism of 1- and 3-nitro-B[a]P has been found to generate multiple pathways for mutagenic activation. The formation of the corresponding trans-7,8-dihydrodiols and 7,8,9,10-tetrahydrotetrols suggests that 1- and 3-nitro-B[a]P trans-7,8-diol-9,10-epoxides are ultimate metabolites of the parent nitro-B[a]Ps. We have isolated a DNA adduct from the reaction between 3-nitro-B[a]P trans-7,8-diol-anti9,10-epoxide and calf thymus DNA, and identified it as 10-(deoxyguanosin-N2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-3-ni tro-B[a]P . The same adduct was identified from in vitro metabolism of [3H]3-nitro-B[a]P by rat liver microsomes in the presence of calf thymus DNA. A DNA adduct of 3-nitro-B[a]P formed from reaction of N-hydroxy-3-amino-B[a]P, prepared in situ with calf thymus DNA was also isolated. This adduct was identified as 6-(deoxyguanosin-N2-yl)-3-amino-B[a]P. The same adduct was obtained from incubating DNA with 3-nitro-B[a]P in the presence of the mammalian nitroeductase, xanthine oxidase, and hypoxanthine.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079-9502.
authors.forename: P P
authors.initials: PP
authors.lastname: Fu
authors.forename: D
authors.initials: D
authors.lastname: Herreno-Saenz
authors.forename: L S
authors.initials: LS
authors.lastname: Von Tungeln
authors.forename: J O
authors.initials: JO
authors.lastname: Lay
authors.forename: Y S
authors.initials: YS
authors.lastname: Wu
authors.forename: J S
authors.initials: JS
authors.lastname: Lai
authors.forename: F E
authors.initials: FE
authors.lastname: Evans
mesh_terms: D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D018736:DNA Adducts / Q000096:biosynthesis*; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D011083:Polycyclic Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens; D011083:Polycyclic Compounds