Mutagenic, cytotoxic, and teratogenic effects of 2-acetylaminofluorene and reactive metabolites in vitro.
The embryotoxic, mutagenic, and cytotoxic properties of 2-acetylaminofluorene (AAF) and two of its reactive metabolites, N-acetoxy-2-acetylaminofluorene (AAAF) and 2-nitrosofluorene (NF) were assessed in vitro. A combined embryo culture/biotransformation system was used to determine the ability of these compounds to produce embryonic malformations, growth retardation, and/or embryolethality. Salmonella typhimurium auxotrophs (his-) were utilized to measure the mutagenic and cytotoxic potentials of these compounds. The parent compound, AAF, did not produce embryonic malformations or mutagenicity in the absence of an added cytochrome P-450-dependent monooxygenase system. Both metabolites produced each of the measured toxic effects without supplementation of a bioactivation system. However, the three chemicals each elicited a different spectrum of malformations. Bioactivated AAF produced neural tube abnormalities, whereas embryos treated with AAAF primarily exhibited prosencephalic malformations, and NF produced abnormalities of axial rotation or flexure. NF was approximately ten times more potent than AAAF as a direct-acting mutagen but only slightly more active in producing embryonic malformations in vitro. The results indicated that differential effects on the various measured parameters could be produced by these chemicals. The results indicated further that neither NF nor AAAF appeared to be individually responsible for the neural tube abnormalities generated by biotransformed AAF.
D015073:2-Acetylaminofluorene / Q000378:metabolism / Q000633:toxicity*; D000014:Abnormalities, Drug-Induced; D000099:Acetoxyacetylaminofluorene / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D009603:Nitroso Compounds / Q000633:toxicity; D010105:Oxygenases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D002273:Carcinogens; D009153:Mutagens; D009603:Nitroso Compounds; C012458:2-nitrosofluorene; D000099:Acetoxyacetylaminofluorene; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene; D010105:Oxygenases