Mutagenicity of the atmospheric transformation products 2-nitrofluoranthene and 2-nitrodibenzopyranone in Salmonella and human cell forward mutation assays.
The mutagenicity of the atmospheric transformation products 2-nitrofluoranthene (2-NF) and 2-nitrodibenzopyranone (2-NDBP), as well as a related isomer 3-nitrodibenzopyranone (3-NDBP), was measured in quantitative forward mutation assays with bacteria (Salmonella typhimurium TM677) and in two metabolically competent human cell lines (MCL-5 and h1A1v2) that differ in their complement of cytochrome P450s and microsomal epoxide hydrolase. 2-NF was a potent mutagen in Salmonella TM677 both in the absence and presence of rat liver postmitochondrial supernatant (PMS). 2-NDBP was non-mutagenic in the absence of PMS, but was mutagenic in its presence. The converse result was obtained for 3-NDBP. The mutagenic potency series in Salmonella in the absence of PMS, expressed as the minimum detectable mutagen concentration (MDMC) in nmol/ml, was: 2-NF, 2.5; 3-NDBP, 16.9; and 2-NDBP, > 415. With PMS, the potency series was: 2-NF, 1.2; 2-NDBP, 15.1; 3-NDBP, 208. Neither 2-NDBP nor 3-NDBP were mutagenic at the tk locus in MCL-5 or h1A1v2 cells at up to 200 nmol/ml. 2-NF was also inactive in MCL-5 cells, but was a potent mutagen in h1A1v2 cells with an MDMC of 0.02 nmol/ml. Cytochrome P450 CYP1A1, present constitutively only in h1A1v2 cells, was implicated in 2-NF activation because mutagenicity was reduced by 55-80% when alpha-naphthoflavone (ANF) was present during incubation. The lack of mutagenicity in MCL-5 cells was attributed to the inability of 2-NF to induce CYP1A1 activity in this cell line. These data indicate a primary role for ring oxidation in 2-NF activation. Previous emphasis placed upon 2-NDBP as a major mutagen in ambient air may need to be modified in view of the negative results for this compound in the human cell assays and in the absence of PMS in Salmonella TM677. However, these findings support the concern that 2-NF may be a risk to human health.
Busby
W F
WF
Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge 02139, USA.
Smith
H
H
Crespi
C L
CL
Penman
B W
BW
Lafleur
A L
AL
D000393:Air Pollutants / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology; D001711:Biotransformation; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D003374:Coumarins / Q000494:pharmacology* / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004790:Enzyme Induction; D005449:Fluorenes / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D000393:Air Pollutants; D003374:Coumarins; D005449:Fluorenes; D009153:Mutagens; D001564:Benzo(a)pyrene; C097142:2-nitro-6H-dibenzo(b,d)pyran-6-one; D019363:Cytochrome P-450 CYP1A1; C049030:2-nitrofluoranthene