Metabolic activation of 2-amino-3-methylimidazo(4,5-f)quinoline by hepatic preparations--contribution of the cytosolic fraction and its significance to strain differences.
In accordance with previous studies the bioactivation of 2-amino-3-methylimidazo(4,5-f)quinoline (IQ) to mutagens in the Ames test was preferentially catalysed by the 3-methyl-cholanthrene-induced cytochromes P-448, in contrast to the phenobarbital-induced forms of the cytochrome. The mutagenicity of IQ catalysed by microsomes, in the absence of cytosol, was much lower when compared with that observed with S9 fractions. Cytosol itself could not activate IQ but markedly potentiated the microsome-mediated mutagenicity of the carcinogen. The effect of the cytosol was still evident when microsomal metabolism was terminated, indicating that the cytosol contains enzyme(s) that can further convert the microsome-generated metabolites of IQ to more potent mutagens. The cytosolic enzyme(s) were inducible by pre-treatment of the rats with Aroclor 1254. The higher efficiency of activation of IQ to mutagens by Sprague-Dawley S9 mixes when compared with similar preparations from the Wistar rat could be attributed not only to differences in the rate of microsomal metabolism but also to the higher ability of the Sprague-Dawley cytosolic fraction in further metabolizing the microsome-generated metabolite(s). The present study demonstrates clearly that the mutagenic response of this compound in the Ames test may be profoundly modulated by the cytosolic fraction and its role in the metabolic activation of pre-mutagens merits further investigation.
Abu-Shakra
A
A
Biochemistry Department, University of Surrey, Guildford, UK.
Ioannides
C
C
Walker
R
R
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001711:Biotransformation; D020111:Chlorodiphenyl (54% Chlorine); D003600:Cytosol / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011804:Quinolines / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013347:Subcellular Fractions / Q000378:metabolism
D001140:Aroclors; D009153:Mutagens; D011804:Quinolines; D009243:NAD; D020111:Chlorodiphenyl (54% Chlorine); C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D008748:Methylcholanthrene; D010634:Phenobarbital