The mutagenicity and interactions of 2- and 4-(acetylamino)fluorene with cytochrome P450 and the aromatic hydrocarbon receptor may explain the difference in their carcinogenic potency.
A study has been undertaken to identify the properties of 2-(acetylamino)fluorene which render it carcinogenic, in contrast to the 4-isomer, the carcinogenic potential of which is, at best, very weak. Compared to the 4-isomer, 2-(acetylamino)fluorene was a more potent inducer of cytochrome P450 1A (P450 1A) activity, as exemplified by the O-deethylation of ethoxyresorufin (P450 1A1), the metabolic activation of Glu-P-1 (P450 1A2), and immunoblot analysis. These findings were consistent with the relative affinity of these compounds for the cytosolic aromatic hydrocarbon receptor, determined by the displacement of tetrachlorodibenzo-p-dioxin. In the presence of Aroclor 1254-induced hepatic microsomal and cytosolic preparations 2-(acetylamino)-fluorene elicited a potent mutagenic response in the Ames test whereas the 4-isomer, in both cases, elicited a weak mutagenic response. Molecular orbital calculations of the relative energetics of the nitrenium ions revealed that the ion of the 2-isomer was more stable than the nitrenium ion of 4-(acetylamino)fluorene. Control hepatic microsomal and cytosolic fractions could activate 2-(acetylamino)fluorene to mutagens in the Ames test. Pretreatment of animals with 2-(acetylamino)fluorene enhanced both the microsome- and cytosol-mediated activation. In contrast, microsomal and cytosolic fractions from control animals could not activate 4-(acetylamino)fluorene, but following pretreatment with the compound itself, a weak mutagenic response in the presence of microsomes, but not of cytosol, was evident.(ABSTRACT TRUNCATED AT 250 WORDS)
Ioannides
C
C
Division of Toxicology, School of Biological Sciences, University of Surrey, Guildford, U.K.
Cheung
Y L
YL
Wilson
J
J
Lewis
D F
DF
Gray
T J
TJ
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002273:Carcinogens / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D015151:Immunoblotting; D066298:In Vitro Techniques; D007536:Isomerism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects*
D001140:Aroclors; D002273:Carcinogens; D009153:Mutagens; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene; C028676:4-acetylaminofluorene