Evaluation of the carcinogenic potential of 2,4-dinitrofluorobenzene and its implications regarding mutagenicity testing.
Tumor promoters are compounds which dramatically enhance the appearance of tumors when chronically applied after an initiating dose of a carcinogen. Initiators are generally considered mutagens while promoters have previously been shown not to induce either DNA damage or mutations. 2,4-Dinitrofluorobenzene (2,4-DNFB), a compound used in the identification of N-terminal amino acids of polypeptides, had been previously reported to be a tumor promoter in mouse skin, while other investigators have found it to be a mutagen in bacteria and yeast. To investigate this apparent discrepancy, we chose to study the carcinogenic potential of 2,4-DNFB utilizing various methods available in V79 Chinese hamster cells. 2,4-DNFB exposure did not result in any unscheduled DNA synthesis a measure of DNA excision repair, nor did it increase the frequency of sister chromatid exchanges in V79 cells either in the presence or absence of rat liver postmitochondrial supernatant (S-15). Forward mutations in V79 cells, either to ouabain or 6-thioguanine resistance, were not induced by 2,4-DNFB, in the presence or absence of S-15. 2,4-DNFB was, however, able to induce reversions in methionine-requiring E. coli auxotrophs in a dose-dependent fashion. Phylogenetic differences between lower organisms and mammals may account for this discordance. 2,4-DNFB was found to inhibit metabolic cooperation, in a dose dependent manner, in V79 cells. This property has previously been shown to be correlated with tumor promoting ability in mouse skin. Therefore, we conclude that the carcinogenic potential of 2,4-DNFB might reside in its ability as a tumor promoter and not as a carcinogenic initiator. Furthermore, these studies serve to illustrate the need for caution when extrapolating bacterial data for risk assessment in humans.
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair; D004139:Dinitrofluorobenzene / Q000633:toxicity*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009154:Mutation; D009578:Nitrobenzenes / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012854:Sister Chromatid Exchange / Q000187:drug effects; D013045:Species Specificity; D014116:Toxicology
D002273:Carcinogens; D009578:Nitrobenzenes; D004247:DNA; D004139:Dinitrofluorobenzene