A cytosolic oxygenase activity involved in the bioactivation of 2-aminofluorene.
The contributions of the hepatic microsomal and cytosolic fractions in the metabolic activation of the promutagen 2-aminofluorene into mutagenic intermediates in the Ames test were investigated. Rat hepatic postmitochondrial, microsomal and cytosolic preparations could convert 2-aminofluorene to mutagens, the postmitochondrial preparation being the most and cytosol the least efficient. Pretreatment of the rats with Aroclor 1254 markedly enhanced the cytosol-mediated mutagenicity of the amine but increased microsomal- and postmitochrondrial-mediated mutagenicity only modestly. The cytosol-mediated mutagenicity of 2-aminofluorene was abolished by heat treatment and by incubation with proteinase K, but was unaffected by dialysis emphasising the protein nature of the cytosolic activation system. Oxygen radical generating systems and oxygen radical scavengers did not significantly influence the cytosol-mediated mutagenic response. Similarly incorporation of xanthine or allopurinol into the cytosolic activation system did not modulate the mutagenic response indicating no role for the molybdenum oxygenases. The cytosolic activation of 2-aminofluorene differed from that mediated by the microsomes in cofactor requirement, substrate specificity and sensitivity to DMSO and (+)-catechin. Further centrifugation of the cytosolic fraction to remove any microsomal contamination did not decrease the cytosolic activation of 2-aminofluorene. It is concluded that the hepatic cytosol contains an oxygenase activity capable of activating certain aromatic amines.
Leist
M
M
Division of Toxicology, School of Biological Sciences, University of Surrey, Guildford, U.K.
Ayrton
A D
AD
Ioannides
C
C
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D020111:Chlorodiphenyl (54% Chlorine); D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D010450:Endopeptidases / Q000494:pharmacology; D005449:Fluorenes / Q000493:pharmacokinetics* / Q000633:toxicity; D006358:Hot Temperature; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D001140:Aroclors; D002273:Carcinogens; D005449:Fluorenes; D009153:Mutagens; D020111:Chlorodiphenyl (54% Chlorine); C012177:2-aminofluorene; D010450:Endopeptidases