title: Metabolic activation of 2- and 3-nitrodibenzopyranone isomers and related compounds by rat liver S9 and the effect of S9 on the mutational specificity of nitrodibenzopyranones.
abstract: The effect of rat liver S9 on the mutagenicity of 10 nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) was evaluated with Salmonella typhimurium TA98NR using S9 from phenobarbital-, 3-methylcholanthrene (MC)-, beta-naphthoflavone- and polychlorobiphenyl-treated and untreated rats. 2-Nitrofluorene (2-NFI), 2-nitrofluoren-9-one (2-NFlone), 2-nitrocarbazole (2-NCz), 3-NCz, 2-nitrodibenzothiophene (2-NDBT), 2-nitro-6H-dibenzo[b,d]pyran-6-one (2-NDBP) and 3-NDBP were metabolically activated by one or more of the S9 fractions, and the highest enhancement of the mutagenic potency of nitro-PAHs was observed with 3-MC-induced S9. Only in the case of 3-NFlone was the mutagenicity in strain TA98NR decreased by the addition of S9, regardless of S9 induction. 2-NDBP was most efficiently activated among nitro-PAHs tested by all S9 fractions used. The cytosolic fraction of S9 accounted for more of the activation of 2-NDBP than the microsomal fraction. NADH and NADPH were the most effective electron donors on the activation of 2-NDBP by S9, 2-NDBP was also metabolically activated by NADH plus commercial preparations of xanthine oxidase. These activations of 2-NDBP were inhibited by allopurinol, indicating that cytosolic xanthine oxidase in rat liver S9 participates in the activation of 2-NDBP. The potency of 2- and 3-NDBP isomers as base-substitution mutagens was also enhanced by S9. In the presence of S9, both compounds showed the highest mutagenicity in strain TA7005 (C.G-->A.T) followed by strains TA7004 (G.C-->A.T), TA7006 (C.G-->G.C) and TA7002 (T.A-->A.T), and this mutation specificity was similar to that without S9, indicating that the mechanism of mutagenesis caused by NDBP isomers with S9 is similar to that without S9.
authors.affiliation: Kyoto Pharmaceutical University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Kaji
authors.forename: M
authors.initials: M
authors.lastname: Takashima
authors.forename: T
authors.initials: T
authors.lastname: Kasai
authors.forename: J
authors.initials: J
authors.lastname: Lewtas
authors.forename: T
authors.initials: T
authors.lastname: Hirayama
mesh_terms: D000818:Animals; D001711:Biotransformation; D003374:Coumarins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004260:DNA Repair; D007536:Isomerism; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D009153:Mutagens; C097142:2-nitro-6H-dibenzo(b,d)pyran-6-one; C097143:3-nitro-6H-dibenzo(b,d)pyran-6-one