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.
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.
Watanabe
T
T
Kyoto Pharmaceutical University, Japan.
Kaji
H
H
Takashima
M
M
Kasai
T
T
Lewtas
J
J
Hirayama
T
T
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
D003374:Coumarins; D009153:Mutagens; C097142:2-nitro-6H-dibenzo(b,d)pyran-6-one; C097143:3-nitro-6H-dibenzo(b,d)pyran-6-one